Fused heterocyclic compounds and uses thereof

ABSTRACT

Disclosed is a harmful arthropod control composition comprising, as an active ingredient, a fused heterocyclic compound represented by formula (1) [wherein A 1  and A 2  independently represent a nitrogen atom or the like; R 1  and R 4  independently represent a halogen atom or the like; R 2  and R 3  independently represent a halogen atom or the like; R 5  and R 6  independently represent a linear C1-C6 hydrocarbon group which may be substituted, or the like (provided that both R 5  and R 6  cannot represent a hydrogen atom simultaneously); and n represents 0 or 1]. The harmful arthropod control composition has an excellent efficacy to control harmful arthropods.

TECHNICAL FIELD

The present invention relates to an arthropod pest control compositionand a condensed heterocyclic compound.

BACKGROUND ART

Various compounds have been studied so far for the purpose ofcontrolling harmful organisms, and such compounds have been practicallyused.

The specification of GB 895,431 A discloses that a benzoxazole compoundis useful as a light-shielding agent and/or a microbicide. Thespecifications of GB 2,311,010 A and JP 49-43974 A disclose abenzoxazole compound as a production intermediate of a pharmaceuticalcompound. Chem. Pharm. Bull., 30(8), 2996 (1982) discloses a certaintype of benzoxazole compound.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a composition havingan excellent controlling effect on arthropod pests.

As a result of intensive studies directed towards achieving theaforementioned object, the present inventors have found that a condensedheterocyclic compound represented by formula (1) has an excellentcontrolling effect on arthropod pests, thereby completing the presentinvention.

Specifically, the present invention includes the following [1] to [18]:

[1] An arthropod pests control composition comprising, as an activeingredient, a condensed heterocyclic compound represented by formula(1):

wherein

each of A¹ and A² independently represents a nitrogen atom or ═C(R⁷)—;

each of R¹ and R⁴ independently represents a halogen atom or a hydrogenatom;

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰;—CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group; a nitrogroup; a halogen atom; or a hydrogen atom;

each of R⁵ and R⁶ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; —OR¹³; —S(O)_(m)R¹³; ahalogen atom; or a hydrogen atom; except that both R⁵ and R⁶ representhydrogen atoms; or R⁵ and R⁶, together with 6-membered ring constituentatoms to which they bind, may form a 5- or 6-membered ring optionallysubstituted with one or more members selected from Group Z;

R⁷ represents a C1-C3 alkyl group optionally substituted with one ormore halogen atoms; a C1-C3 alkoxy group optionally substituted with oneor more halogen atoms; a cyano group; a halogen atom; or a hydrogenatom;

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C4-C7 cycloalkylmethyl group optionally substituted with oneor more members selected from Group X; a C3-C6 alicyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a phenyl group optionally substituted with one or more membersselected from Group Y; a benzyl group optionally substituted with one ormore members selected from Group Y; a 5- or 6-membered heterocyclicgroup optionally substituted with one or more members selected fromGroup Y; or a hydrogen atom; provided that R⁸ does not represent ahydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

each of R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; or a hydrogenatom;

each of R¹¹ and R¹² independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C2-C4alkoxycarbonyl group; or a hydrogen atom;

R¹³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; or a C3-C6 alicyclichydrocarbon group optionally substituted with one or more membersselected from Group X;

R¹⁵ represents a C1-C4 alkyl group optionally substituted with one ormore halogen atoms;

m represents 0, 1, or 2;

n represents 0 or 1;

Group X: the group consisting of a C1-C4 alkoxy group optionallysubstituted with one or more halogen atoms; a cyano group; and a halogenatom;

Group Y: the group consisting of a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C1-C4 alkoxy groupoptionally substituted with one or more halogen atoms; a cyano group; anitro group; and a halogen atom; and

Group Z: the group consisting of a C1-C3 alkyl group optionallysubstituted with one or more halogen atoms; and a halogen atom;

[2] The arthropod pest control composition according to [1] above,wherein the condensed heterocyclic compound is the compound wherein

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —CONR¹⁰NR¹¹R¹²; a cyanogroup; a nitro group; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y; or a hydrogen atom;

[3] The arthropod pest control composition according to [1] or [2]above, wherein the condensed heterocyclic compound is the compoundwherein R¹ and R⁴ represent a hydrogen atom;[4] The arthropod pest control composition according to [1], [2], or [3]above, wherein the condensed heterocyclic compound is the compoundwherein R² represents a hydrogen atom or a halogen atom;[5] The arthropod pest control composition according to [1], [2], [3],or [4] above, wherein the condensed heterocyclic compound is thecompound wherein R³ represents a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; or a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;[6] The arthropod pest control composition according [1], [3], or [4]above, wherein the condensed heterocyclic compound is the compoundwherein

R³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰;—CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group; a nitrogroup; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

[7] The arthropod pest control composition according to [1], [2], [3],or [4] above, wherein the condensed heterocyclic compound is thecompound wherein

R³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; —OR⁸; —NR⁸R⁹;—S(O)_(m)R⁸; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

[8] The arthropod pest control composition according to [1], [2], [3],[4], [5], [6], or [7] above, wherein the condensed heterocyclic compoundis the compound wherein

each of R⁵ and R⁶ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; —OR¹³; —S(O)_(m)R¹³; a halogen atom; or a hydrogen atom;wherein at least one of R⁵ and R⁶ represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; —OR¹³; —S(O)_(m)R¹³; or a halogen atom; and

R¹³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X;

[9] An arthropod pest control method, which comprises applying, toarthropod pests or areas where arthropod pests live, an effective amountof a condensed heterocyclic compound represented by formula (1):

wherein

each of A¹ and A² independently represents a nitrogen atom or ═C(R⁷)—;

each of R¹ and R⁴ independently represents a halogen atom or a hydrogenatom;

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰;—CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group; a nitrogroup; a halogen atom; or a hydrogen atom;

each of R⁵ and R⁶ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; —OR¹³; —S(O)_(m)R¹³; ahalogen atom; or a hydrogen atom; except that both R⁵ and R⁶ representhydrogen atoms; or R⁵ and R⁶, together with 6-membered ring constituentatoms to which they bind, may form a 5- or 6-membered ring optionallysubstituted with one or more members selected from Group Z;

R⁷ represents a C1-C3 alkyl group optionally substituted with one ormore halogen atoms; a C1-C3 alkoxy group optionally substituted with oneor more halogen atoms; a cyano group; a halogen atom; or a hydrogenatom;

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C4-C7 cycloalkylmethyl group optionally substituted with oneor more members selected from Group X; a C3-C6 alicyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a phenyl group optionally substituted with one or more membersselected from Group Y; a benzyl group optionally substituted with one ormore members selected from Group Y; a 5- or 6-membered heterocyclicgroup optionally substituted with one or more members selected fromGroup Y; or a hydrogen atom; provided that R⁸ does not represent ahydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

each of R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; or a hydrogenatom;

each of R¹¹ and R¹² independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C2-C4alkoxycarbonyl group; or a hydrogen atom;

R¹³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; or a C3-C6 alicyclichydrocarbon group optionally substituted with one or more membersselected from Group X;

R¹⁵ represents a C1-C4 alkyl group optionally substituted with one ormore halogen atoms;

m represents 0, 1, or 2;

n represents 0 or 1;

Group X: the group consisting of a C1-C4 alkoxy group optionallysubstituted with one or more halogen atoms; a cyano group; and a halogenatom;

Group Y: the group consisting of a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C1-C4 alkoxy groupoptionally substituted with one or more halogen atoms; a cyano group; anitro group; and a halogen atom; and

Group Z: the group consisting of a C1-C3 alkyl group optionallysubstituted with one or more halogen atoms; and a halogen atom;

[10] The arthropod pest control method according to [9] above, whereinthe arthropod pests are Hemiptera insect pests;[11] A condensed heterocyclic compound represented by formula (2):

wherein

each of A¹ and A² independently represents a nitrogen atom or ═C(R⁷)—;

each of R¹ and R⁴ independently represents a halogen atom or a hydrogenatom;

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰;—CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰R¹²; a cyano group; a nitrogroup; a halogen atom; or a hydrogen atom;

each of R^(5a) and R^(6a) independently represents a C1-C6 acyclichydrocarbon group which is substituted with one or more halogen atoms; aC3-C6 alicyclic hydrocarbon group which is substituted with one or morehalogen atoms; —OR^(13a); —S(O)_(m)R^(13a); a halogen atom; or ahydrogen atom; except that both R^(5a) and R^(6a) represent membersselected from the group consisting of a halogen atom and a hydrogenatom; or R^(5a) and R^(6a), together with 6-membered ring constituentatoms to which they bind, may form a 5- or 6-membered ring which issubstituted with one or more halogen atoms;

R⁷ represents a C1-C3 alkyl group optionally substituted with one ormore halogen atoms; a C1-C3 alkoxy group optionally substituted with oneor more halogen atoms; a cyano group; a halogen atom; or a hydrogenatom;

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C4-C7 cycloalkylmethyl group optionally substituted with oneor more members selected from Group X; a C3-C6 alicyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a phenyl group optionally substituted with one or more membersselected from Group Y; a benzyl group optionally substituted with one ormore members selected from Group Y; a 5- or 6-membered heterocyclicgroup optionally substituted with one or more members selected fromGroup Y; or a hydrogen atom; provided that R⁸ does not represent ahydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

each of R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; or a hydrogenatom;

each of R¹¹ and R¹² independently represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C2-C4alkoxycarbonyl group; or a hydrogen atom;

R^(13a) represents a C1-C6 acyclic hydrocarbon group which issubstituted with one or more halogen atoms; or a C3-C6 alicyclichydrocarbon group which is substituted with one or more halogen atoms;

R¹⁵ represents a C1-C4 alkyl group optionally substituted with one ormore halogen atoms;

m represents 0, 1, or 2;

n represents 0 or 1;

Group X: the group consisting of a C1-C4 alkoxy group optionallysubstituted with one or more halogen atoms; a cyano group; and a halogenatom; and

Group Y: the group consisting of a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C1-C4 alkoxy groupoptionally substituted with one or more halogen atoms; a cyano group; anitro group; and a halogen atom;

[12] The condensed heterocyclic compound according to [11] above,wherein

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —CONR¹⁰NR¹¹R¹²; a cyanogroup; a nitro group; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y; or a hydrogen atom; provided that R⁸ doesnot represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

[13] The condensed heterocyclic compound according to [11] or [12]above, wherein R¹ and R⁴ represent a hydrogen atom;[14] The condensed heterocyclic compound according to [11], [12], or[13] above, wherein R² represents a hydrogen atom or a halogen atom;[15] The condensed heterocyclic compound according to [11], [12], [13],or [14] above, wherein R³ represents a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; or a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;[16] The condensed heterocyclic compound according to [11], [13], or[14] above, wherein

R³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰;—CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group; a nitrogroup; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

[17] The condensed heterocyclic compound according to [11], [12], [13],or [14] above, wherein

R³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; —OR⁸; —NR⁸R⁹;—S(O)_(m)R⁸; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2; and

[18] The condensed heterocyclic compound according to [11], [12], [13],[14], [15], [16], or [17] above, wherein

at least one of R^(5a) and R^(6a) represents a C1-C6 acyclic hydrocarbongroup which is substituted with one or more halogen atoms; or —OR^(13a);and

R^(13a) represents a C1-C6 acyclic hydrocarbon group which issubstituted with one or more halogen atoms.

Hereinafter, the condensed heterocyclic compound represented by theformula (1) may be referred to as “the present active compound”, and thearthropod pest control composition of the present invention may bereferred to as “the composition of the present invention,” at times.

ADVANTAGES OF THE INVENTION

The composition of the present invention has an excellent effect ofcontrolling arthropod pests, and it has an excellent controlling effecton such arthropod pests.

BEST MODE FOR CARRYING OUT THE INVENTION

Substituents used in the present active compound will be describedbelow, while giving the examples.

In the present specification, for example, the term “C4-C7” used in theexpression “C4-C7 cycloalkylmethyl group” means that the total number ofcarbon atoms constituting the cycloalkylmethyl group is within the rangefrom 4 to 7.

The “halogen atom” means a fluorine atom, a chlorine atom, a bromineatom, and an iodine atom.

Examples of the “C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X” represented by R² or R³include:

C1-C6 alkyl groups such as a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, an isobutyl group, a sec-butylgroup, a tert-butyl group, a pentyl group, and a hexyl group;

C1-C6 alkyl groups substituted with one or more members selected fromGroup X, such as a methoxymethyl group, an ethoxymethyl group, and atrifluoromethyl group;

C2-C6 alkenyl groups such as an ethenyl group, a 1-propenyl group, a2-propenyl group, a 1-methylethenyl group, a 2-methyl-1-propenyl group,a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-pentenylgroup, and a 1-hexenyl group;

C2-C6 alkenyl groups substituted with one or more members selected fromGroup X;

C2-C6 alkynyl groups such as ethynyl group, a propargyl group, a2-butynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynylgroup; and C2-C6 alkynyl groups substituted with one or more membersselected from Group X.

Examples of the “C3-C6 alicyclic hydrocarbon group optionallysubstituted with one or more members selected from Group X” representedby R² or R³ include a cyclopropyl group, a cyclobutyl group, acyclopentyl group, and a cyclohexyl group.

Examples of the “phenyl group optionally substituted with one or moremembers selected from Group Y” represented by R² or R³ include a phenylgroup, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenylgroup, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenylgroup, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a4-methoxyphenyl group, a 2-(trifluoromethyl)phenyl group, a3-(trifluoromethyl)phenyl group, a 4-(trifluoromethyl)phenyl group, a2-nitrophenyl group, a 3-nitrophenyl group, a 4-nitrophenyl group, a2-cyanophenyl group, a 3-cyanophenyl group, and a 4-cyanophenyl group.

Examples of the “benzyl group optionally substituted with one or moremembers selected from Group Y” represented by R² or R³ include a benzylgroup, a 2-chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzylgroup, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzylgroup, a 2-methoxybenzyl group, a 3-methoxybenzyl group, and a4-methoxybenzyl group.

Examples of the “5-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y” represented by R² or R³include:

5-membered saturated heterocyclic groups such as a pyrrolidin-1-yl groupand a tetrahydrofuran-2-yl group; and

5-membered aromatic heterocyclic groups such as a pyrazol-1-yl group, a3-chloro-pyrazol-1-yl group, a 3-bromopyrazol-1-yl group, a3-nitropyrazol-1-yl group, a 3-methylpyrazol-1-yl group, a3-(trifluoromethyl)pyrazol-1-yl group, a 4-methylpyrazol-1-yl group, a4-chloropyrazol-1-yl group, a 4-bromopyrazol-1-yl group, a4-cyanopyrazol-1-yl group, an imidazol-1-yl group, a4-(trifluoromethyl)imidazol-1-yl group, a pyrrol-1-yl group, a1,2,4-triazol-1-yl group, a 3-chloro-1,2,4-triazol-1-yl group, a1,2,3,4-tetrazol-1-yl group, a 1,2,3,5-tetrazol-1-yl group, a 2-thienylgroup, and a 3-thienyl group.

Examples of the “6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y” represented by R² or R³include:

6-membered saturated heterocyclic groups such as a piperidyl group, amorpholyl group, a thiomorpholyl group, and a 4-methylpiperazin-1-ylgroup; and

6-membered aromatic heterocyclic groups such as a 2-pyridyl group, a3-pyridyl group, and a 4-pyridyl group.

Examples of the “C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X” represented by R⁵ or R⁶include:

C1-C6 alkyl groups such as a methyl group, an ethyl group, a propylgroup, an isopropyl group, an isobutyl group, a sec-butyl group, atert-butyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropylgroup, and a 1-ethylpropyl group;

C1-C6 alkyl groups substituted with one or more members selected fromGroup X, such as a methoxymethyl group, a 1-methoxyethyl group, a1,1-difluoroethyl group, a trifluoromethyl group, a pentafluoroethylgroup, and a heptafluoroisopropyl group;

C2-C6 alkenyl groups such as an ethenyl group, a 1-propenyl group, a2-propenyl group, a 1-methylethenyl group, a 1-methyl-1-propenyl group,a 1-methyl-2-propenyl group, a 1-butenyl group, a 2-butenyl group, and a3-butenyl group;

C2-C6 alkenyl groups substituted with one or more members selected fromGroup X;

C2-C6 alkynyl groups such as an ethynyl group, a propargyl group, a2-butynyl group, and a 3-butynyl group; and

C2-C6 alkynyl groups substituted with one or more members selected fromGroup X. A preferred example is a C1-C4 alkyl group substituted with oneor more halogen atoms, and a more preferred example is a trifluoromethylgroup.

Examples of the “C3-C6 alicyclic hydrocarbon group optionallysubstituted with one or more members selected from Group X” representedby R⁵ or R⁶ include a cyclopropyl group, a 1-methylcyclopropyl group, acyclobutyl group, a cyclopentyl group, a 1-methylcyclopentyl group, a1-cyclopentenyl group, and a cyclohexyl group.

Examples of the 5- or 6-membered ring formed with R⁵ and R⁶, togetherwith 6-membered ring constituent atoms to which they bind, include therings represented by the formulae (a), (b), (c), (d), (e), (f), (g),(h), and (i) as shown below, wherein A⁵ represents a 6-membered ringcarbon atom to which R⁵ binds, and A⁶ represents a 6-membered ringcarbon atom to which R⁶ binds.

Examples of the “C1-C3 alkyl group optionally substituted with one ormore halogen atoms” represented by R⁷ include a methyl group, an ethylgroup, a propyl group, an isopropyl group, and a trifluoromethyl group.

Examples of the “C1-C3 alkoxy group optionally substituted with one ormore halogen atoms” represented by R⁷ include a methoxy group, an ethoxygroup, an isopropoxy group, a trifluoromethoxy group, and adifluoromethoxy group.

Examples of the “C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X” represented by R⁸ or R⁹include:

C1-C6 alkyl groups such as a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, an isobutyl group, a sec-butylgroup, a tert-butyl group, a 1-methylbutyl group, a 2-methylbutyl group,a 3-methylbutyl group, a 1-ethylpropyl group, a 1,2-dimethylpropylgroup, a 2,2-dimethylpropyl group, a pentyl group, a 1,2-dimethylbutylgroup, a 2,2-dimethylbutyl group, a 1-methylpentyl group, a2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group,and a hexyl group;

C1-C6 alkyl groups substituted with one or more members selected fromGroup X, such as a cyanomethyl group, a difluoromethyl group, atrifluoromethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethylgroup, and a 1-methyl-2,2,2-trifluoroethyl group;

C3-C6 alkenyl groups such as a 2-propenyl group, a 1-methyl-2-propenylgroup, a 2-methyl-2-propenyl group, a 2-butenyl group, a 3-butenylgroup, a 1-methyl-2-butenyl group, and a 1-methyl-3-butenyl group;

C3-C6 alkenyl groups substituted with one or more members selected fromGroup X, such as a 3,3-dichloro-2-propenyl group and a3,3-difluoro-2-propenyl group;

C3-C6 alkynyl groups such as a propargyl group, a 1-methyl-2-propynylgroup, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-butynyl group,and a 1-methyl-3-butynyl group; and

C3-C6 alkynyl groups substituted with one or more members selected fromGroup X.

Examples of the C4-C7 cycloalkylmethyl group represented by R⁸ or R⁹include a cyclopropylmethyl group, a cyclobutylmethyl group, acyclopentylmethyl group, and a cyclohexylmethyl group.

Examples of the C3-C6 alicyclic hydrocarbon group represented by R⁸ orR⁹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,a cyclohexyl group, and a 2-cyclohexenyl group.

Examples of the “phenyl group optionally substituted with one or moremembers selected from Group Y” represented by R⁸ or R⁹ include a2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group,a 2-(trifluoromethyl)phenyl group, a 3-(trifluoromethyl)phenyl group, a4-(trifluoromethyl)phenyl group, a 2-cyanophenyl group, a 3-cyanophenylgroup, a 4-cyanophenyl group, a 2-nitrophenyl group, a 3-nitrophenylgroup, and a 4-nitrophenyl group.

Examples of the “benzyl group optionally substituted with one or moremembers selected from Group Y” represented by R⁸ or R⁹ include a benzylgroup, a 2-chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzylgroup, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzylgroup, a 2-methoxybenzyl group, a 3-methoxybenzyl group, and a4-methoxybenzyl group.

Examples of the “5-membered heterocyclic group” represented by R⁸ or R⁹include 5-membered aromatic heterocyclic groups such as a 2-thienylgroup and a 3-thienyl group.

Examples of the “6-membered heterocyclic group” represented by R⁸ or R⁹include 6-membered aromatic heterocyclic groups such as a 2-pyridylgroup, a 3-pyridyl group, a 4-pyridyl group, a 2-pyrimidinyl group, anda 4-pyrimidinyl group.

Examples of the “C1-C4 alkyl group” represented by R¹⁰ or R¹⁴ include amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, and a tert-butylgroup.

Examples of the “C1-C4 alkyl group optionally substituted with one ormore halogen atoms” represented by R¹¹ or R¹² include a methyl group, anethyl group, a 2,2,2-trifluoroethyl group, a propyl group, an isopropylgroup, a butyl group, an isobutyl group, a sec-butyl group, and atert-butyl group.

Examples of the “C2-C4 alkoxycarbonyl group” represented by R¹¹ or R¹²include a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, and an isopropoxycarbonyl group.

Examples of the “C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X” represented by R¹³include:

C1-C6 alkyl groups such as a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, an isobutyl group, a sec-butylgroup, a 1-methylbutyl group, and a 2-methylbutyl group;

C1-C6 alkyl groups substituted with one or more members selected fromGroup X, such as a difluoromethyl group, a trifluoromethyl group, and a2,2,2-trifluoroethyl group;

C3-C6 alkenyl groups such as a 2-propenyl group, a 1-methyl-2-propenylgroup, a 2-methyl-2-propenyl group, a 2-butenyl group, and a 3-butenylgroup;

C3-C6 alkenyl groups substituted with one or more members selected fromGroup X, such as a 2-chloro-2-propenyl group, a 3,3-difluoro-2-propenylgroup, and a 3,3-dichloro-2-propenyl group;

C3-C6 alkynyl groups such as a propargyl group, a 1-methyl-2-propynylgroup, a 2-butynyl group, and a 3-butynyl group; and C3-C6 alkynylgroups substituted with one or more members selected from Group X. Apreferred example is a C1-C4 alkyl group substituted with one or morehalogen atoms, and a more preferred example is a trifluoromethyl group.

Examples of the “C3-C6 alicyclic hydrocarbon group optionallysubstituted with one or more members selected from Group X” representedby R¹³ include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, and a 2-cyclohexenyl group.

Examples of the “C1-C4 alkyl group” represented by R¹⁵ include a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a sec-butyl group, and a tert-butyl group.

One embodiment of the present active compound is the compoundrepresented by formula (2), for example:

wherein A¹, A², R¹, R², R³, R⁴, and n have the same meaning as definedabove,

each of R^(5a) and R^(6a) independently represents a C1-C6 acyclichydrocarbon group which is substituted with one or more halogen atoms; aC3-C6 alicyclic hydrocarbon group which is substituted with one or morehalogen atoms; —OR^(13a); —S(O)_(m)R^(13a); a halogen atom; or ahydrogen atom; except that both R^(5a) and R^(6a) represent membersselected from the group consisting of a halogen atom and a hydrogenatom; or R^(5a) and R^(6a), together with 6-membered ring constituentatoms to which they bind, may form a 5- or 6-membered ring which issubstituted with one or more halogen atoms; and

R^(13a) represents a C1-C6 acyclic hydrocarbon group which issubstituted with one or more halogen atoms; or a C3-C6 alicyclichydrocarbon group which is substituted with one or more halogen atoms.

Examples of the “C1-C6 acyclic hydrocarbon group which is substitutedwith one or more halogen atoms” represented by R^(5a) or R^(6a) includea 1,1-difluoroethyl group, a trifluoromethyl group, a pentafluoroethylgroup, and a heptafluoroisopropyl group. Of these, a trifluoromethylgroup is preferable.

Examples of the C3-C6 alicyclic hydrocarbon group represented by R^(5a)or R^(6a) include a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, and a cyclohexyl group.

Examples of the “5- or 6-membered ring substituted with one or morehalogen atoms” which is formed with R^(5a) and R^(6a), together with6-membered ring constituent atoms to which they bind, include the ringsrepresented by the formulae (j), (k), (l), (m), (n), (o), (p), (q), (r),and (s) as shown below, wherein A⁵ represents a 6-membered ring carbonatom to which R^(5a) binds, and A⁶ represents a 6-membered ring carbonatom to which R^(6a) binds.

Examples of the “C1-C6 acyclic hydrocarbon group which is substitutedwith one or more halogen atoms” represented by R^(13a) include atrifluoromethyl group, a difluoromethyl group, and a2,2,2-trifluoroethyl group. Of these, a trifluoromethyl group ispreferable.

Examples of the C3-C6 alicyclic hydrocarbon group in the “C3-C6alicyclic hydrocarbon group which is substituted with one or morehalogen atoms” represented by R^(13a) include a cyclopropyl group, acyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

One embodiment of the present invention is a composition comprising atleast one of the following compounds as an active ingredient, forexample:

a compound, wherein, in the formula (1),

each of R² and R³ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y; —OR⁸; —NR⁸R⁹;—NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —CONR¹⁰NR¹¹R¹²; a cyanogroup; a nitro group; a halogen atom; or a hydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y, or a hydrogen atom, provided that R⁸ doesnot represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

a compound, wherein, in the formula (1), R¹ and R⁴ represent a hydrogenatom;

a compound, wherein, in the formula (1), R² represents a hydrogen atomor a halogen atom;

a compound, wherein, in the formula (1), R³ represents a C3-C6 alicyclichydrocarbon group optionally substituted with one or more membersselected from Group X, a phenyl group optionally substituted with one ormore members selected from Group Y; a benzyl group optionallysubstituted with one or more members selected from Group Y; or a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y;

a compound, wherein, in the formula (1), R³ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; —OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴;—NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰;—CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogen atom; or ahydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

a compound, wherein, in the formula (1), R³ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; —OR⁸; —NR⁸R⁹; —S(O)_(m)R⁸; a halogen atom; or ahydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

a compound, wherein, in the formula (1),

each of R⁵ and R⁶ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; —OR¹³; —S(O)_(m)R¹³; a halogen atom; or a hydrogen atom; exceptthat both R⁵ and R⁶ represent hydrogen atoms; and

R¹³ represents a C1-C6 acyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X;

a compound, wherein, in the formula (1), R⁵ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more halogen atoms,or —OR¹³, and R¹³ represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁶ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more halogen atoms,or —OR¹³, and R¹³ represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms, or —OR¹³,and R¹³ represents a C1-C6 acyclic hydrocarbon group substituted withone or more halogen atoms;

a compound, wherein, in the formula (1), R⁶ represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms, or —OR¹³,and R¹³ represents a C1-C6 acyclic hydrocarbon group substituted withone or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a trifluoromethylgroup;

a compound, wherein, in the formula (1), R⁵ represents a tert-butylgroup;

a compound, wherein, in the formula (1), R⁶ represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁶ represents a trifluoromethylgroup;

a compound, wherein, in the formula (1), R⁶ represents a tert-butylgroup;

a compound, wherein, in the formula (1), R⁵ represents —OR¹³, and R¹³represents a C1-C6 acyclic hydrocarbon group substituted with one ormore halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents —OR¹³, and R¹³represents a trifluoromethyl group or a difluoromethyl group;

a compound, wherein, in the formula (1), R⁶ represents —OR¹³, and R¹³represents a C1-C6 acyclic hydrocarbon group substituted with one ormore halogen atoms;

a compound, wherein, in the formula (1), R⁶ represents —OR¹³, and R¹³represents a trifluoromethyl group or a difluoromethyl group;

a compound, wherein, in the formula (1), R⁵ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more halogen atoms,and R⁶ represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents —OR′³, R¹³represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more halogen atoms, and R⁶ represents a hydrogen atom or ahalogen atom;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, and R⁶ represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, R⁶ represents —OR¹³, and R¹³ represents a C1-C6acyclic hydrocarbon group optionally substituted with one or morehalogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms, R⁶represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents —OR¹³, R¹³represents a C1-C6 acyclic hydrocarbon group substituted with one ormore halogen atoms, and R⁶ represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, and R⁶ represents a C1-C6 acyclic hydrocarbon groupsubstituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, R⁶ represents —OR¹³, and R¹³ represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms;

a compound, wherein, in the formula (1), R⁵ represents a trifluoromethylgroup, and R⁶ represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents a tert-butylgroup, and R⁶ represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents —OR¹³, R¹³represents a trifluoromethyl group or a difluoromethyl group, and R⁶represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, and R⁶ represents a trifluoromethyl group;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, and R⁶ represents a tert-butyl group;

a compound, wherein, in the formula (1), R⁵ represents a hydrogen atomor a halogen atom, R⁶ represents —OR¹³, and R¹³ represents atrifluoromethyl group or a difluoromethyl group;

a compound, wherein, in the formula (1), A¹ represents a nitrogen atom,A² represents ═C(R⁷)—, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (1), A¹ represents ═C(R⁷)—, A²represents a nitrogen atom, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (1), A¹ and A² each represent═C(R⁷)—, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (1), each of R² and R³ independentlyrepresents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms; a C2-C4 alkoxyalkyl group; a C2-C4 alkenyl group; apyrrolidyl group; a piperidyl group; a morpholyl group; an imidazolylgroup; a pyrazolyl group; a triazolyl group; a (C1-C3 alkylgroup)-substituted pyrazolyl group; a (C1-C3 halogenated alkylgroup)-substituted pyrazolyl group; a phenyl group; a pyridyl group;—OR^(8a), wherein R^(8a) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms, a C3-C4 alkenyl groupoptionally substituted with one or more halogen atoms, a C3-C4 alkynylgroup, a benzyl group, a C2-C4 alkoxyalkyl group, a C4-C7cycloalkylmethyl group, or a hydrogen atom; —NR^(8b)R^(9a), wherein eachof R^(8b) and R^(9a) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms, or a hydrogen atom;—NHC(O)R^(9b), wherein R^(9b) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; —NHCO₂R^(15a), whereinR^(15a) represents a C1-C4 alkyl group; —S(O)_(m1)R^(8c), wherein R^(8c)represents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms, and m1 represents 1 or 2; —SR^(8d), wherein R^(8d)represents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms, or a hydrogen atom; a cyano group; a halogen atom; or ahydrogen atom;

a compound, wherein, in the formula (1), each of R² and R³ independentlyrepresents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms, —OR^(8a), wherein R^(8a) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; —NR^(8b)R^(9a),wherein each of R^(8b) and R^(9a) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, or a hydrogenatom; —S(O)_(m1)R^(8c), wherein R^(8C) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, and m1 represents1 or 2; —SR^(8d), wherein R^(8d) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, or a hydrogenatom; a halogen atom; or a hydrogen atom;

a compound, wherein, in the formula (1), at least one of R⁵ and R⁶represents a C1-C3 alkyl group substituted with one or more halogenatoms, a C1-C4 alkyl group, or —OR^(13a), and R^(13a) represents a C1-C3alkyl group substituted with one or more halogen atoms;

a compound, wherein, in the formula (2), each of R² and R³ independentlyrepresents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a C3-C6 alicyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a phenyl group optionally substituted with one or more membersselected from Group Y; a benzyl group optionally substituted with one ormore members selected from Group Y; a 5- or 6-membered heterocyclicgroup optionally substituted with one or more members selected fromGroup Y; —OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹;—CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogen atom; or ahydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; a C3-C6 alicyclic hydrocarbon group optionally substituted withone or more members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y; or a hydrogen atom; provided that R⁸ doesnot represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2;

a compound, wherein, in the formula (2), R¹ and R⁴ represent a hydrogenatom;

a compound, wherein, in the formula (2), R² represents a hydrogen atomor a halogen atom;

a compound, wherein, in the formula (2), R³ represents a C3-C6 alicyclichydrocarbon group optionally substituted with one or more membersselected from Group X; a phenyl group optionally substituted with one ormore members selected from Group Y; a benzyl group optionallysubstituted with one or more members selected from Group Y; or a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y;

a compound, wherein, in the formula (2), R³ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; —OR^(B); —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴;—NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰;—CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogen atom; or ahydrogen atom; and each of R⁸ and R⁹ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; or a hydrogen atom; provided that R⁸represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X when m in —S(O)_(m)R⁸ is 1 or2;

a compound, wherein, in the formula (2), R³ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; —OR⁸; —NR⁸R⁹; —S(O)_(m)R⁸; a halogen atom; or ahydrogen atom; and

each of R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbongroup optionally substituted with one or more members selected fromGroup X; or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or 2;

a compound, wherein, in the formula (2), R^(5a) represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms, or—OR^(13a), and R^(13a) represents a C1-C6 acyclic hydrocarbon groupsubstituted with one or more halogen atoms;

a compound, wherein, in the formula (2), R^(6a) represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms, or—OR^(13a), and R^(13a) represents a C1-C6 acyclic hydrocarbon groupsubstituted with one or more halogen atoms;

a compound, wherein, in the formula (2), R^(5a) represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms, acompound, wherein, in the formula (2), R^(5a) represents atrifluoromethyl group;

a compound, wherein, in the formula (2), R^(6a) represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms;

a compound, wherein, in the formula (2), R^(6a) represents atrifluoromethyl group;

a compound, wherein, in the formula (2), R^(5a) represents —OR^(13a),and R^(13a) represents a C1-C6 acyclic hydrocarbon group substitutedwith one or more halogen atoms;

a compound, wherein, in the formula (2), R^(5a) represents —OR^(13a),and R^(13a) represents a trifluoromethyl group or a difluoromethylgroup;

a compound, wherein, in the formula (2), R^(6a) represents —OR^(13a),and R^(13a) represents a C1-C6 acyclic hydrocarbon group substitutedwith one or more halogen atoms;

a compound, wherein, in the formula (2), R^(6a) represents —OR^(13a),and R^(13a) represents a trifluoromethyl group or a difluoromethylgroup;

a compound, wherein, in the formula (2), R^(5a) represents a C1-C6acyclic hydrocarbon group substituted with one or more halogen atoms,and R^(6a) represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (2), R^(5a) represents —OR^(13a),R^(13a) represents a C1-C6 acyclic hydrocarbon group substituted withone or more halogen atoms, and R^(6a) represents a hydrogen atom or ahalogen atom;

a compound, wherein, in the formula (2), R^(5a) represents a hydrogenatom or a halogen atom, and R^(6a) represents a C1-C6 acyclichydrocarbon group substituted with one or more halogen atoms;

a compound, wherein, in the formula (2), R^(5a) represents a hydrogenatom or a halogen atom, R^(6a) represents —OR^(13a), and R^(13a)represents a C1-C6 acyclic hydrocarbon group substituted with one ormore halogen atoms;

a compound, wherein, in the formula (2), R^(5a) represents atrifluoromethyl group, and R^(6a) represents a hydrogen atom or ahalogen atom;

a compound, wherein, in the formula (2), R^(5a) represents —OR^(13a),R^(13a) represents a trifluoromethyl group or a difluoromethyl group,and R^(6a) represents a hydrogen atom or a halogen atom;

a compound, wherein, in the formula (2), R^(5a) represents a hydrogenatom or a halogen atom, and R^(5a) represents a trifluoromethyl group;

a compound, wherein, in the formula (2), R^(5a) represents a hydrogenatom or a halogen atom, R^(6a) represents —OR^(13a), and R^(13a)represents a trifluoromethyl group or a difluoromethyl group;

a compound, wherein, in the formula (2), A¹ represents a nitrogen atom,A² represents ═C(R⁷)—, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (2), A¹ represents ═C(R⁷)—, A²represents a nitrogen atom, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (2), A¹ and A² each represent═C(R⁷)—, and R⁷ represents a hydrogen atom;

a compound, wherein, in the formula (2), each of R² and R³ independentlyrepresents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms; a C2-C4 alkoxyalkyl group; a C2-C4 alkenyl group; apyrrolidyl group; a piperidyl group; a morpholyl group; an imidazolylgroup; a pyrazolyl group; a triazolyl group; a (C1-C3 alkylgroup)-substituted pyrazolyl group; a (C1-C3 halogenated alkylgroup)-substituted pyrazolyl group; a phenyl group; a pyridyl group;—OR^(8a), wherein R^(8a) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms, a C3-C4 alkenyl groupoptionally substituted with one or more halogen atoms, a C3-C4 alkynylgroup, a benzyl group, a C2-C4 alkoxyalkyl group, a C4-C7cycloalkylmethyl group, or a hydrogen atom; —NR^(8b)R^(9a), wherein eachof R^(8b) and R^(9a) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms, or a hydrogen atom;—NHC(O)R^(9b), wherein R^(9b) represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; —NHCO₂R^(15a), whereinR^(15a) represents a C1-C4 alkyl group; —S(O)_(m1)R^(8c), wherein R^(8c)represents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms, and m1 represents 1 or 2; —SR^(8d), wherein R^(8d)represents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms, or a hydrogen atom; a cyano group; a halogen atom; or ahydrogen atom;

a compound, wherein, in the formula (2), each of R² and R³ independentlyrepresents a C1-C4 alkyl group optionally substituted with one or morehalogen atoms; —OR^(8a), wherein R^(8a) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; —NR^(8b)R^(9a),wherein each of R^(8b) and R^(9a) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, or a hydrogenatom; —S(O)_(m1)R^(8c), wherein R^(8c) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, and m1 represents1 or 2; —SR^(8d), wherein R^(8d) represents a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms, or a hydrogenatom; a halogen atom; or a hydrogen atom; and

a compound, wherein, in the formula (2), at least one of R^(5a) andR^(6a) represents a C1-C3 alkyl group substituted with one or morehalogen atoms, or —OR^(13a), and R^(13a) represents a C1-C3 alkyl groupsubstituted with one or more halogen atoms.

Next, a method for producing the present active compound will bedescribed.

The present active compound can be produced, for example, by thefollowing (Production Method 1) to (Production Method 14).

In each production method, a compound represented by a specific formulamay be indicated in the form of the compound followed by the number ofthe formula in parentheses. For example, a compound represented byformula (3) may be referred to as “compound (3).”

(Production Method 1)

A compound (5), i.e., a compound of the formula (1) wherein n is 0, canbe produced by reacting a compound (3) with a compound (4) in thepresence of an acid,

wherein R¹, R², R³ _(,) R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

Examples of the acid include polyphosphoric acid and trimethylsilylpolyphosphate.

When polyphosphoric acid is used as an acid, the reaction is generallycarried out in the absence of a solvent. However, the reaction may alsobe carried out in a solvent.

Examples of the solvent include: ethers such as tetrahydrofuran(hereinafter referred to as THF, at times), ethylene glycol dimethylether, or 1,4-dioxane; aromatic hydrocarbons such as toluene or xylene;halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; andthe mixtures thereof.

The compound (4) is generally used at a ratio of 1 to 3 moles relativeto 1 mole of the compound (3).

The reaction temperature applied to the reaction is generally between50° C. and 200° C., and the reaction time is generally between 0.5 and24 hours.

After completion of the reaction, water is added to the reactionmixture, and the mixture is then extracted with an organic solvent. Theorganic layer is subjected to a post-treatment such as drying orconcentration, so as to isolate the compound (5). The isolated compound(5) can be further purified by chromatography, recrystallization, etc.

(Production Method 2)

The above compound (5) can be produced by reacting a compound (6) in thepresence of an oxidizer,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aliphatic hydrocarbons such as hexane orheptane; aromatic hydrocarbons such as toluene or xylene; halogenatedhydrocarbons such as dichloromethane, chloroform, or chlorobenzene;esters such as ethyl acetate or butyl acetate; alcohols such as methanolor ethanol; nitriles such as acetonitrile; acid amides such asN,N-dimethylformamide (hereinafter referred to as DMF, at times);sulfoxides such as dimethyl sulfoxide (hereinafter referred to as DMSO,at times); acetic acids; and the mixtures thereof.

Examples of the oxidizer include: metallic oxidizers such as lead(IV)acetate or lead(IV) oxide; and organic periodides such as iodobenzenediacetate.

Such oxidizer is generally used at a ratio of 1 to 3 moles relative to 1mole of the compound (6).

The reaction temperature applied to the reaction is generally between 0°C. and 100° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5). The isolated compound (5) can be further purified bychromatography, recrystallization, etc.

(Production Method 3)

The above compound (5) can be produced by reacting a compound (7) in thepresence of a dehydration-condensation agent,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride, or chlorobenzene; esters such as ethyl acetate orbutyl acetate; nitriles such as acetonitrile; and the mixtures thereof.Of these, carbon tetrachloride can also be used as adehydration-condensation agent.

Examples of the dehydration-condensation agent include: a mixture oftriphenylphosphine, a base, and carbon tetrachloride or carbontetrabromide; and a mixture of triphenylphosphine and an azodiester suchas azodicarboxylic acid diethyl ester.

Examples of the base include tertiary amines such as triethylamine ordiisopropylethylamine.

The dehydration-condensation agent is generally used at a ratio of 1 to3 moles relative to 1 mole of the compound (7). The base is generallyused at a ratio of 1 to 5 moles relative to 1 mole of the compound (7).

The reaction temperature applied to the reaction is generally between−30° C. and +100° C., and the reaction time is generally between 0.5 and24 hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5). The isolated compound (5) can be further purified bychromatography, recrystallization, etc.

(Production Method 4)

The above compound (5) can be produced by reacting the compound (7) inthe presence of an acid,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; halogenated hydrocarbons such as dichloromethane, chloroform, orchlorobenzene; and the mixtures thereof.

Examples of the acid include: sulfonic acids such as p-toluenesulfonicacid; and polyphosphoric acid.

Such acid is generally used at a ratio of 0.1 to 3 moles relative to 1mole of the compound (7).

The reaction temperature applied to the reaction is generally between50° C. and 200° C., and the reaction time is generally between 1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5). The isolated compound (5) can be further purified bychromatography, recrystallization, etc.

(Production Method 5)

A compound (5-a), i.e., a compound of the formula (1) wherein n is 0 andR³ is —OR⁸, can be produced by reacting a compound (8) with a compound(9) in the presence of a base,

wherein R¹, R², R⁴, R⁵, R⁶, R⁸, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent. Itmay also be possible to use the compound (9) in a solvent amount.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (9) is generally used at a ratio of 1 to 100 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (8).

The reaction temperature applied to the reaction is generally between 0°C. and 120° C., and the reaction time is generally between 0.5 and 24hours.

After completion of this reaction, known reactions such as ahydrogenation reaction, an oxidation reaction, and a reduction reaction,may be further carried out to convert R⁸ arbitrarily.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-a). The isolated compound (5-a) can be further purified bychromatography, recrystallization, etc.

(Production Method 6)

A compound (5-b), i.e., a compound of the formula (1) wherein n is 0 andR³ is —SR⁸, can be produced by reacting the compound (8) with a compound(10) in the presence of a base,

wherein R¹, R², R⁴, R⁵, R⁶, R⁸, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (10) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (8).

The reaction temperature applied to the reaction is generally between 0°C. and 100° C., and the reaction time is generally between 0.5 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-b). The isolated compound (5-b) can be further purified bychromatography, recrystallization, etc.

After completion of this reaction, an oxidation reaction known to aperson skilled in the art may be further carried out, so that —SR⁸ canbe converted to —S(O)_(m1)R⁸ wherein m1 is 1 or 2.

(Production Method 7)

A compound (5-c), i.e., a compound of the formula (1) wherein n is 0 andR³ is —NR⁸R⁹, can be produced by reacting the compound (8) with acompound (11) in the presence of a base,

wherein R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (II) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (8).

The reaction temperature applied to the reaction is generally between 0°C. and 100° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-c). The isolated compound (5-c) can be further purified bychromatography, recrystallization, etc.

(Production Method 8)

A compound (5-d), i.e., a compound of the formula (1) wherein n is 0 andR³ is —NR⁸COR⁹, can be produced by reacting a compound (12) with an acidanhydride represented by a formula (13) or an acid chloride representedby a formula (14),

wherein R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; nitrogen-containing aromatic compounds such aspyridine or quinoline; and the mixtures thereof. When the reaction isthe reaction of the compound (12) with the compound (13), the compound(13) may be used in a solvent amount, instead of the above exemplifiedsolvents.

The reaction may also be carried out in the presence of a base, asnecessary.

Examples of the base include: alkali metal hydrides such as sodiumhydride; carbonates such as potassium carbonate; tertiary amines such astriethylamine or diisopropylethylamine; and nitrogen-containing aromaticcompounds such as pyridine or 4-dimethylaminopyridine.

The compound (13) or the compound (14) is generally used at a ratio of 1to 10 moles relative to 1 mole of the compound (12). When the reactionis carried out in the presence of a base, the base is generally used ata ratio of 1 to 10 moles relative to 1 mole of the compound (12).

The reaction temperature applied to the reaction is generally between 0°C. and 120° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-d). The isolated compound (5-d) can be further purified bychromatography, recrystallization, etc.

(Production Method 9)

A compound (5-e), i.e., a compound of the formula (1) wherein n is 0 andR³ is —R^(3x) as shown below, can be produced by reacting a compound(15) with a boronic acid compound represented by a formula (16) or a tincompound represented by a formula (17) in the presence of a palladiumcompound,

wherein R¹, R², R⁴, R⁵, R⁶, A¹ and A² have the same meaning as definedabove, L represents a bromine atom or an iodine atom, and

R^(3x) represents a phenyl group optionally substituted with one or moremembers selected from Group Y, or a 5-membered aromatic heterocyclicgroup or 6-membered aromatic heterocyclic group optionally substitutedwith one or more members selected from Group Y wherein the aromaticheterocyclic group is limited to an aromatic heterocyclic group thatbinds to a pyridine ring on a carbon atom.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; alcohols such as methanol or ethanol;aliphatic hydrocarbons such as hexane, heptane, or octane; aromatichydrocarbons such as toluene or xylene; acid amides such as DMF; water;and the mixtures thereof.

Examples of the palladium compound include palladium acetate,tetrakistriphenylphosphine palladium, a{1,1′-bis(diphenylphosphino)ferrocene}dichloropalladium dichloromethanecomplex, and dichlorobis(triphenylphosphine)palladium(II).

The compound (16) or the compound (17) is generally used at a ratio of0.5 to 5 moles, and the palladium compound is generally used at a ratioof 0.001 to 0.1 mole, relative to 1 mole of the compound (15).

The reaction may also be carried out in the presence of a base and/or aphase transfer catalyst, as necessary.

Examples of the base include inorganic salts such as sodium acetate,potassium acetate, potassium carbonate, tripotassium phosphate, orsodium bicarbonate.

Examples of the phase transfer catalyst include quaternary ammoniumsalts such as tetrabutylammonium bromide or benzyltriethylammoniumbromide.

The amount of the base or phase transfer catalyst may be selected, asappropriate, depending on the type of a compound used, and the like.

The reaction temperature applied to the reaction is generally between50° C. and 120° C., and the reaction time is generally between 0.5 and24 hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-e). The isolated compound (5-e) can be further purified bychromatography, recrystallization, etc.

(Production Method 10)

A compound (5-f), i.e., a compound of the formula (1) wherein n is 0 andR³ is R^(3y) as shown below, can be produced by reacting the compound(8) with a compound (18) in the presence of a base,

wherein R¹, R², R⁴, R⁵, R⁶, A¹, and A² have the same meaning as definedabove, and

R^(3y) represents a 5- or 6-membered heterocyclic group optionallysubstituted with one or more members selected from Group Y wherein theheterocyclic group is limited to a heterocyclic group that binds to apyridine ring on a nitrogen atom.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (18) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (8).

The reaction temperature applied to the reaction is generally between 0°C. and 150° C., and the reaction time is generally between 0.1 and 24hours.

After completion of this reaction, known reactions such as ahydrogenation reaction, an oxidation reaction, a reduction reaction, anda hydrolysis reaction may be further carried out to convert R^(3y)arbitrarily.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-f). The isolated compound (5-f) can be further purified bychromatography, recrystallization, etc.

(Production Method 11)

A compound (19), i.e., a compound of the formula (1) wherein n is 1, canbe produced by reacting the compound (5) in the presence of an oxidizer,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: aliphatic halogenated hydrocarbons suchas dichloromethane or chloroform; acetic acids, water; and the mixturesthereof.

Examples of the oxidizer include: peroxycarboxylic acids, such as3-chloroperbenzoic acid; and a hydrogen peroxide solution.

Such oxidizer is generally used at a ratio of 1 to 3 moles relative to 1mole of the compound (5).

The reaction temperature applied to the reaction is generally between−20° C. and +100° C., and the reaction time is generally between 0.1 and24 hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is washed with anaqueous solution of a reducing agent and an aqueous solution of a base,as necessary, and it is then subjected to a post-treatment such asdrying or concentration, so as to isolate the compound (19). Theisolated compound (19) can be further purified by chromatography,recrystallization, etc.

Examples of the reducing agent include sodium sulfite and sodiumthiosulfate. An example of the base is sodium bicarbonate.

(Production Method 12)

A compound (5-a), i.e., a compound of the formula (1) wherein n is 0 andR³ is —OR⁸, can be produced by reacting a compound (20) with a compound(21) in the presence of a base,

wherein R¹, R², R⁴, R⁵, R⁶, R⁸, A¹, and A² have the same meaning asdefined above, and X represents a leaving group such as a chlorine atom,a bromine atom, an iodine atom, —OS(O)₂CF₃ and —OS(O)₂CH₃.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF,sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (21) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (20).

The reaction temperature applied to the reaction is generally between 0°C. and 120° C., and the reaction time is generally between 0.5 and 24hours.

After completion of this reaction, known reactions such as ahydrogenation reaction, an oxidation reaction, and a reduction reaction,may be further carried out to convert R⁸ arbitrarily.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-a). The isolated compound (5-a) can be further purified bychromatography, recrystallization, etc.

(Production Method 13)

A compound represented by the formula (5-g) can be produced by reactingthe compound (15) with a compound (22) in the presence of a palladiumcompound, a base, and a copper salt,

wherein R¹, R², R⁴, R⁵, R⁶, A¹, A², and L have the same meaning asdefined above, and R^(3z) represents a C1-C4 acyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X.

This reaction is generally carried out using a base as a solvent. Anauxiliary solvent may also be used.

Examples of the base include amines such as triethylamine, diethylamine,or diisopropylethylamine.

Examples of the auxiliary solvent include: ethers such as THF, ethyleneglycol dimethyl ether, or 1,4-dioxane; acid amides such as DMF; and themixtures thereof.

Examples of the palladium compound include tetrakistriphenylphosphinepalladium, a {1,1′-bis(diphenylphosphino)ferrocene}dichloropalladiumdichloromethane complex, anddichlorobis(triphenylphosphine)palladium(II).

An example of the copper salt is copper(I) iodide.

The compound (22) is generally used at a ratio of 0.5 to 5 moles, thepalladium compound is generally used at a ratio of 0.001 to 0.1 mole,and the copper salt is used at a ratio of 0.001 to 0.1, relative to 1mole of the compound (15).

In addition to the palladium compound, base, and copper salt, acoordination compound capable of coordinating with the palladiumcompound may be further used to carry out the reaction.

Examples of the coordination compound include phosphines such astriphenylphosphine or tri(tert-butyl)phosphine.

The reaction temperature applied to the reaction is generally between 0°C. and 100° C., and the reaction time is generally between 0.5 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-g). The isolated compound (5-g) can be further purified bychromatography, recrystallization, etc.

After completion of this reaction, known reactions such as ahydrogenation reaction, an oxidation reaction, a reduction reaction, anda hydrolysis reaction may be further carried out, so as to arbitrarilyconvert R^(3z), and a triple bond that binds the R^(3z) with a pyridinering.

A compound (23), wherein, in a formula (22), R^(3z) is a trimethylsilylgroup, is reacted with the compound (15) in the presence of a palladiumcompound, a base, and a copper salt. A known desilylation reaction isfurther carried out on the compound obtained from the reaction, so as toobtain a compound (5-g1), wherein, in a formula (5-g), R^(3z) is ahydrogen atom. The compound (5g-1) is subjected to a known reaction suchas a hydrogenation reaction, so as to convert the triple bondarbitrarily.

(Production Method 14)

A compound (5-h), i.e., a compound of the formula (1) wherein n is 0 andR³ is a cyano group, can be produced by reacting the compound (15) witha metal cyanide,

wherein R¹, R², R⁴, R⁵, R⁶, A¹, A², and L have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; acid amides such as DMF or1-methyl-2-pyrrolidinone; sulfoxides such as DMSO; and the mixturesthereof.

An example of the metal cyanide is copper(I) cyanide.

Such metal cyanide is generally used at a ratio of 1 to 5 moles relativeto 1 mole of the compound (15).

The reaction temperature applied to the reaction is generally between50° C. and 200° C., and the reaction time is generally between 0.5 and24 hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (5-h). The isolated compound (5-h) can be further purified bychromatography, recrystallization, etc.

An intermediate used in the production of the present active compound iscommercially available, or is disclosed in known publications, or can beproduced according to a method known to a person skilled in the art.

The intermediate of the present invention can be produced, for example,by the following methods.

(Intermediate Production Method 1)

wherein R⁵, R⁶, A¹, and A² have the same meaning as defined above.

(Step 1)

The compound (M2) can be produced by reacting the compound (M1) in thepresence of a nitrating agent.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: aliphatic halogenated hydrocarbons suchas chloroform; acetic acid; concentrated sulfuric acid; concentratednitric acid; water; and the mixtures thereof.

An example of the nitrating agent is concentrated nitric acid.

Such nitrating agent is generally used at a ratio of 1 to 3 molesrelative to 1 mole of the compound (M1).

The reaction temperature applied to the reaction is generally between−10° C. and +80° C., and the reaction time is generally between 0.1 and24 hours.

After completion of the reaction, the reaction mixture is added towater, and it is then extracted with an organic solvent. Thereafter, theorganic layer is subjected to a post-treatment such as drying orconcentration, so as to isolate the compound (M2). The isolated compound(M2) can be further purified by chromatography, recrystallization, etc.

(Step 2)

The compound (3) can be produced by reacting the compound (M2) withhydrogen in the presence of a catalyst for hydrogenation.

This reaction is generally carried out in a hydrogen atmosphere under 1to 100 atmospheric pressures in the presence of a solvent.

Examples of the solvent used in the reaction include: ethers such as THFor 1,4-dioxane; esters such as ethyl acetate or butyl acetate; alcoholssuch as methanol or ethanol; water; and the mixtures thereof.

Examples of the catalyst for hydrogenation include transition metalcompounds such as palladium on carbon, palladium hydroxide, Raneynickel, or platinum oxide.

The hydrogen is generally used at a ratio of 3 moles, and the catalystfor hydrogenation is generally used at a ratio of 0.001 to 0.5 moles,relative to 1 mole of the compound (M2).

An acid, a base, and the like may be added, as necessary, to carry outthe reaction.

The reaction temperature applied to the reaction is generally between−20° C. and +100° C., and the reaction time is generally between 0.1 and24 hours.

After completion of the reaction, the reaction mixture is filtrated, andit is then extracted with an organic solvent, as necessary. Thereafter,the organic layer is subjected to a post-treatment such as drying orconcentration, so as to isolate the compound (3). The isolated compound(3) can be further purified by chromatography, recrystallization, etc.

(Intermediate Production Method 2)

The compound (6) can be produced by reacting the compound (3) with acompound (M3),

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: alcohols such as methanol or ethanol;ethers such as THF, ethylene glycol dimethyl ether, or 1,4-dioxane;aromatic hydrocarbons such as toluene; and the mixtures thereof.

The compound (M3) is generally used at a ratio of 0.5 to 3 molesrelative to 1 mole of the compound (3).

An acid, a base, and the like may be added, as necessary, to carry outthe reaction.

The reaction temperature applied to the reaction is generally between 0°C. and 150° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (6). The isolated compound (6) can be further purified bychromatography, recrystallization, etc.

(Intermediate Production Method 3)

The compound (7) can be produced by reacting the compound (3) with thecompound (4) in the presence of a dehydration-condensation agent,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aliphatic hydrocarbons such as hexane,heptane, or octane; aromatic hydrocarbons such as toluene or xylene;halogenated hydrocarbons such as chlorobenzene; esters such as ethylacetate or butyl acetate; nitriles such as acetonitrile; acid amidessuch as DMF; sulfoxides such as DMSO; nitrogen-containing aromaticcompounds such as pyridine or quinoline; and the mixtures thereof.

Examples of the dehydration-condensation agent include: carbodiimidessuch as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(hereinafter referred to as WSC) or 1,3-dicyclohexylcarbodiimide; and(benzotriazol-1-yl-oxy)tris(dimethylamino)phosphoniumhexafluorophosphate (hereinafter referred to as a BOP reagent).

The compound (4) is generally used at a ratio of 1 to 3 moles, and thedehydration-condensation agent is generally used at a ratio of 1 to 5moles, relative to 1 mole of the compound (3).

The reaction temperature applied to the reaction is generally between 0°C. and 140° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, water is added to the reactionmixture, and it is then extracted with an organic solvent. Thereafter,the organic layer is subjected to a post-treatment such as drying orconcentration, so as to isolate the compound (7). The isolated compound(7) can be further purified by chromatography, recrystallization, etc.

(Intermediate Production Method 4)

The compound (7) can be produced by reacting the compound (3) with acompound (M4) in the presence of a base,

wherein R¹, R², R³, R⁴, R⁵, R⁶, A¹, and A² have the same meaning asdefined above.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aliphatic hydrocarbons such as hexane,heptane, or octane; aromatic hydrocarbons such as toluene or xylene;halogenated hydrocarbons such as chlorobenzene; esters such as ethylacetate or butyl acetate; nitriles such as acetonitrile; acid amidessuch as DMF; sulfoxides such as DMSO; and the mixtures thereof.

Examples of the base include: alkali metal carbonates such as sodiumcarbonate or potassium carbonate; tertiary amines such as triethylamineor diisopropylethylamine; and nitrogen-containing aromatic compoundssuch as pyridine or 4-dimethylaminopyridine.

The compound (M4) is generally used at a ratio of 1 to 3 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (3).

The reaction temperature applied to the reaction is generally between−20° C. and +100° C., and the reaction time is generally between 0.1 and24 hours.

After completion of the reaction, water is added to the reactionmixture, and it is then extracted with an organic solvent. Thereafter,the organic layer is subjected to a post-treatment such as drying orconcentration, so as to isolate the compound (7). The isolated compound(7) can be further purified by chromatography, recrystallization, etc.

(Intermediate Production Method 5)

A compound (4-a), wherein, in a formula (4), R¹, R², and R⁴ represent ahyrdrogen atom, and R³ represents the following —R^(3p), can be producedby a method as shown in the following scheme,

wherein R^(3p) represents a C1-C6 acyclic hydrocarbon group optionallysubstituted with one or more members selected from Group X, and a C3-C6alicyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X, and Group X has the same meaning asdefined above.

(Step 1)

The compound (M6) can be produced by reacting the compound (M5) in thepresence of an oxidizer.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: aliphatic halogenated hydrocarbons suchas dichloromethane or chloroform; acetic acid; water; and the mixturesthereof.

Example of the oxidizer include peroxycarboxylic acids, such as3-chloroperbenzoic acid; and a hydrogen peroxide solution.

Such oxidizer is generally used at a ratio of 1 to 10 moles relative to1 mole of the compound (M5).

The reaction temperature applied to the reaction is generally between−20° C. and +120° C., and the reaction time is generally between 0.1 and24 hours.

After completion of the reaction, a base is added to the reactionmixture, as necessary, to neutralize it. Thereafter, the reactionmixture is extracted with an organic solvent, and the organic layer isthen washed with an aqueous solution of a reducing agent and an aqueoussolution of a base, as necessary, followed by a post-treatment such asdrying or concentration, so as to isolate the compound (M6). Theisolated compound (M6) can be further purified by chromatography,distillation, etc.

Examples of the base include alkali metal carbonates such as sodiumcarbonate, sodium bicarbonate, or potassium carbonate. Examples of thereducing agent include sodium sulfite, sodium hydrogen sulfite, andsodium thiosulfate

(Step 2)

The compound (M7) can be produced by reacting the compound (M6) in thepresence of an alkylating agent and a cyaniding agent.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as 1,4-dioxane; water; andthe mixtures thereof.

Examples of the alkylating agent include iodomethane, iodoethane, anddimethyl sulfate.

Examples of the cyaniding agent include sodium cyanide and potassiumcyanide. The alkylating agent is generally used at a ratio of 1 to 10moles, and the

cyaniding agent is generally used at a ratio of 1 to 3 moles, relativeto 1 mole of the compound (M6).

The reaction temperature applied to the reaction is generally between 0°C. and 100° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (M7). The isolated compound (M7) can be further purified bychromatography, recrystallization, etc.

(Step 3)

The compound (4-a) can be produced by subjecting the compound (M7) to ahydrolysis reaction in the presence of a base.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, tert-butyl methyl ether, or 1,4-dioxane; alcohols suchas methanol or ethanol; water; and the mixtures thereof.

Examples of the base include alkali metal hydroxides such as sodiumhydroxide or potassium hydroxide.

Such base is generally used at a ratio of 1 to 10 moles relative to 1mole of the compound (M7).

The reaction temperature applied to the reaction is generally between 0°C. and 120° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction solution is converted toan acidic solution, and the reaction mixture is then extracted with anorganic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (4-a). The isolated compound (4-a) can be further purified bychromatography, recrystallization, etc.

(Intermediate Production Method 6)

A compound (4-b), wherein, in the formula (4), R³ represents thefollowing —OR⁸, can be produced by a method as shown in the followingscheme,

wherein R¹, R², R⁴, and R⁸ have the same meaning as defined above.

(Step 1)

The compound (M9) can be produced by reacting the compound (M8) with thecompound (9) in the presence of a base.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Example of the base include alkali metal hydrides such as sodiumhydride.

The compound (9) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (M8).

The reaction temperature applied to the reaction is generally between−20° C. and +100° C., and the reaction time is generally between 0.5 and24 hours.

After completion of this reaction, known reactions such as ahydrogenation reaction, an oxidation reaction, and a reduction reactionmay be further carried out to convert R⁸ arbitrarily.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (M9). The isolated compound (M9) can be further purified bychromatography, recrystallization, etc.

(Step 2)

The compound (4-b) can be produced by subjecting the compound (M9) to ahydrolysis reaction in the presence of a base.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, tert-butyl methyl ether, or 1,4-dioxane; alcohols suchas methanol or ethanol; water; and the mixtures thereof.

Examples of the base include alkali metal hydroxides such as sodiumhydroxide or potassium hydroxide.

Such base is generally used at a ratio of 1 to 10 moles relative to 1mole of the compound (M9).

The reaction temperature applied to the reaction is generally between 0°C. and 120° C., and the reaction time is generally between 0.1 and 24hours.

After completion of the reaction, the reaction solution is converted toan acidic solution, and the reaction mixture is then extracted with anorganic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (4-b). The isolated compound (4-b) can be further purified bychromatography, recrystallization, etc.

(Intermediate Production Method 7)

A compound (4-c), wherein, in the formula (4), R³ represents thefollowing —SR⁸, can be produced by a method as shown in the followingscheme,

wherein R¹, R², R⁴, and R⁸ have the same meaning as defined above.

(Step 1)

The compound (M11) can be produced by reacting the compound (M10) withthe compound (10) in the presence of a base.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, or 1,4-dioxane; aromatic hydrocarbons such as toluene orxylene; nitriles such as acetonitrile; acid amides such as DMF;sulfoxides such as DMSO; and the mixtures thereof.

Example of the base include: alkali metal hydrides such as sodiumhydride; and carbonates such as potassium carbonate.

The compound (10) is generally used at a ratio of 1 to 10 moles, and thebase is generally used at a ratio of 1 to 10 moles, relative to 1 moleof the compound (M10).

The reaction temperature applied to the reaction is generally between−20° C. and +100° C., and the reaction time is generally between 0.5 and24 hours.

After completion of the reaction, the reaction mixture is extracted withan organic solvent, and the organic layer is then subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (M11). The isolated compound (M11) can be further purified bychromatography, recrystallization, etc.

(Step 2)

The compound (4-c) can be produced by subjecting the compound (M11) to ahydrolysis reaction in the presence of a base.

This reaction is generally carried out in the presence of a solvent.

Examples of the solvent include: ethers such as THF, ethylene glycoldimethyl ether, tert-butyl methyl ether, or 1,4-dioxane; alcohols suchas methanol or ethanol; water; and the mixtures thereof.

Examples of the base include alkali metal hydroxides such as sodiumhydroxide or potassium hydroxide.

Such base is generally used at a ratio of 1 to 10 moles relative to 1mole of the compound (M11). The reaction temperature applied to thereaction is generally between 0° C. and 120° C., and the reaction timeis generally between 0.1 and 24 hours.

After completion of the reaction, the reaction solution is converted toan acidic solution, and the reaction mixture is then extracted with anorganic solvent. Thereafter, the organic layer is subjected to apost-treatment such as drying or concentration, so as to isolate thecompound (4-c). The isolated compound (4-c) can be further purified bychromatography, recrystallization, etc.

Next, specific examples of the present active compound will be givenbelow.

In the following tables, Me represents a methyl group, Et represents anethyl group, Pr represents a propyl group, iPr represents an isopropylgroup, tBu represents a tert-butyl group, Ph represents a phenyl group,2-Py represents a 2-pyridyl group, 3-Py represents a 3-pyridyl group,4-Py represents a 4-pyridyl group, 1-Tz represents a 1,2,4-triazol-1-ylgroup, and 1-Pz represents a pyrazol-1-yl group.

The compound represented by the following formula (1-A):

In the above formula (1-A), substituents used for R³, R⁵, R⁶, R⁷, A²,and n are available in the combinations shown in the following (Table 1)to (Table 35).

TABLE 1 R³ R⁵ R⁶ R⁷ A² n H tBu H H ═C(H)— 0 F tBu H H ═C(H)— 0 Cl tBu HH ═C(H)— 0 Br tBu H H ═C(H)— 0 I tBu H H ═C(H)— 0 Me tBu H H ═C(H)— 0 EttBu H H ═C(H)— 0 Pr tBu H H ═C(H)— 0 MeO tBu H H ═C(H)— 0 EtO tBu H H═C(H)— 0 PrO tBu H H ═C(H)— 0 CF₃CH₂O tBu H H ═C(H)— 0 iPrO tBu H H═C(H)— 0 MeS tBu H H ═C(H)— 0 EtS tBu H H ═C(H)— 0 PrS tBu H H ═C(H)— 0CF₃CH₂S tBu H H ═C(H)— 0 iPrS tBu H H ═C(H)— 0 Ph tBu H H ═C(H)— 0 2-PytBu H H ═C(H)— 0 3-Py tBu H H ═C(H)— 0 4-Py tBu H H ═C(H)— 0 1-Tz tBu HH ═C(H)— 0 1-Pz tBu H H ═C(H)— 0

TABLE 2 R³ R⁵ R⁶ R⁷ A² n H tBu H H ═C(H)— 1 Cl tBu H H ═C(H)— 1 Br tBu HH ═C(H)— 1 I tBu H H ═C(H)— 1 Me tBu H H ═C(H)— 1 Et tBu H H ═C(H)— 1 PrtBu H H ═C(H)— 1 MeO tBu H H ═C(H)— 1 EtO tBu H H ═C(H)— 1 PrO tBu H H═C(H)— 1 CF₃CH₂O tBu H H ═C(H)— 1 iPrO tBu H H ═C(H)— 1 Ph tBu H H═C(H)— 1 H CF₃ H H ═C(H)— 0 F CF₃ H H ═C(H)— 0 Cl CF₃ H H ═C(H)— 0 BrCF₃ H H ═C(H)— 0 I CF₃ H H ═C(H)— 0 Me CF₃ H H ═C(H)— 0 Et CF₃ H H═C(H)— 0 Pr CF₃ H H ═C(H)— 0 MeO CF₃ H H ═C(H)— 0 EtO CF₃ H H ═C(H)— 0PrO CF₃ H H ═C(H)— 0

TABLE 3 R³ R⁵ R⁶ R⁷ A² n CF₃CH₂O CF₃ H H ═C(H)— 0 iPrO CF₃ H H ═C(H)— 0MeS CF₃ H H ═C(H)— 0 EtS CF₃ H H ═C(H)— 0 PrS CF₃ H H ═C(H)— 0 CF₃CH₂SCF₃ H H ═C(H)— 0 iPrS CF₃ H H ═C(H)— 0 Ph CF₃ H H ═C(H)— 0 2-Py CF₃ H H═C(H)— 0 3-Py CF₃ H H ═C(H)— 0 4-Py CF₃ H H ═C(H)— 0 1-Tz CF₃ H H ═C(H) 0 1-Pz CF₃ H H ═C(H)— 0 H CF₃ H H ═C(H)— 1 Cl CF₃ H H ═C(H)— 1 Br CF₃ HH ═C(H)— 1 I CF₃ H H ═C(H)— 1 Me CF₃ H H ═C(H)— 1 Et CF₃ H H ═C(H)— 1 PrCF₃ H H ═C(H)— 1 MeO CF₃ H H ═C(H)— 1 EtO CF₃ H H ═C(H)— 1 PrO CF₃ H H═C(H)— 1 CF₃CH₂O CF₃ H H ═C(H)— 1

TABLE 4 R³ R⁵ R⁶ R⁷ A² n iPrO CF₃ H H ═C(H)— 1 Ph CF₃ H H ═C(H)— 1 H CF₃Cl H ═C(H)— 0 F CF₃ Cl H ═C(H)— 0 Cl CF₃ Cl H ═C(H)— 0 Br CF₃ Cl H═C(H)— 0 I CF₃ Cl H ═C(H)— 0 Me CF₃ Cl H ═C(H)— 0 Et CF₃ Cl H ═C(H)— 0Pr CF₃ Cl H ═C(H)— 0 MeO CF₃ Cl H ═C(H)— 0 EtO CF₃ Cl H ═C(H)— 0 PrO CF₃Cl H ═C(H)— 0 CF₃CH₂O CF₃ Cl H ═C(H)— 0 iPrO CF₃ Cl H ═C(H)— 0 MeS CF₃Cl H ═C(H)— 0 EtS CF₃ Cl H ═C(H)— 0 PrS CF₃ Cl H ═C(H)— 0 CF₃CH₂S CF₃ ClH ═C(H)— 0 iPrS CF₃ Cl H ═C(H)— 0 Ph CF₃ Cl H ═C(H)— 0 2-Py CF₃ Cl H═C(H)— 0 3-Py CF₃ Cl H ═C(H)— 0 4-Py CF₃ Cl H ═C(H)— 0

TABLE 5 R³ R⁵ R⁶ R⁷ A² n 1-Tz CF₃ Cl H ═C(H)— 0 1-Pz CF₃ Cl H ═C(H)— 0 HCF₃ Cl H ═C(H)— 1 Cl CF₃ Cl H ═C(H)— 1 Br CF₃ Cl H ═C(H)— 1 I CF₃ Cl H═C(H)— 1 Me CF₃ Cl H ═C(H)— 1 Et CF₃ Cl H ═C(H)— 1 Pr CF₃ Cl H ═C(H)— 1MeO CF₃ Cl H ═C(H)— 1 EtO CF₃ Cl H ═C(H)— 1 PrO CF₃ Cl H ═C(H)— 1CF₃CH₂O CF₃ Cl H ═C(H)— 1 iPrO CF₃ Cl H ═C(H)— 1 Ph CF₃ Cl H ═C(H)— 1 HCF₃ H Cl ═C(H)— 0 F CF₃ H Cl ═C(H)— 0 Cl CF₃ H Cl ═C(H)— 0 Br CF₃ H Cl═C(H)— 0 I CF₃ H Cl ═C(H)— 0 Me CF₃ H Cl ═C(H)— 0 Et CF₃ H Cl ═C(H)— 0Pr CF₃ H Cl ═C(H)— 0 MeO CF₃ H Cl ═C(H)— 0

TABLE 6 R³ R⁵ R⁶ R⁷ A² n EtO CF₃ H Cl ═C(H)— 0 PrO CF₃ H Cl ═C(H)— 0CF₃CH₂O CF₃ H Cl ═C(H)— 0 iPrO CF₃ H Cl ═C(H)— 0 MeS CF₃ H Cl ═C(H)— 0EtS CF₃ H Cl ═C(H)— 0 PrS CF₃ H Cl ═C(H)— 0 CF₃CH₂S CF₃ H Cl ═C(H)— 0iPrS CF₃ H Cl ═C(H)— 0 Ph CF₃ H Cl ═C(H)— 0 2-Py CF₃ H Cl ═C(H)— 0 3-PyCF₃ H Cl ═C(H)— 0 4-Py CF₃ H Cl ═C(H)— 0 1-Tz CF₃ H Cl ═C(H)— 0 1-Pz CF₃H Cl ═C(H)— 0 H CF₃ H Cl ═C(H)— 1 Cl CF₃ H Cl ═C(H)— 1 Br CF₃ H Cl═C(H)— 1 I CF₃ H Cl ═C(H)— 1 Me CF₃ H Cl ═C(H)— 1 Et CF₃ H Cl ═C(H)— 1Pr CF₃ H Cl ═C(H)— 1 MeO CF₃ H Cl ═C(H)— 1 EtO CF₃ H Cl ═C(H)— 1

TABLE 7 R³ R⁵ R⁶ R⁷ A² n PrO CF₃ H Cl ═C(H)— 1 CF₃CH₂O CF₃ H Cl ═C(H)— 1iPrO CF₃ H Cl ═C(H)— 1 Ph CF₃ H Cl ═C(H)— 1 H CF₃ H H ═N— 0 F CF₃ H H═N— 0 Cl CF₃ H H ═N— 0 Br CF₃ H H ═N— 0 I CF₃ H H ═N— 0 Me CF₃ H H ═N— 0Et CF₃ H H ═N— 0 Pr CF₃ H H ═N— 0 MeO CF₃ H H ═N— 0 EtO CF₃ H H ═N— 0PrO CF₃ H H ═N— 0 CF₃CH₂O CF₃ H H ═N— 0 iPrO CF₃ H H ═N— 0 MeS CF₃ H H═N— 0 EtS CF₃ H H ═N— 0 PrS CF₃ H H ═N— 0 CF₃CH₂S CF₃ H H ═N— 0 iPrS CF₃H H ═N— 0 Ph CF₃ H H ═N— 0 2-Py CF₃ H H ═N— 0

TABLE 8 R³ R⁵ R⁶ R⁷ A² n 3-Py CF₃ H H ═N— 0 4-Py CF₃ H H ═N— 0 1-Tz CF₃H H ═N— 0 1-Pz CF₃ H H ═N— 0 H CF₃O H H ═C(H)— 0 F CF₃O H H ═C(H)— 0 ClCF₃O H H ═C(H)— 0 Br CF₃O H H ═C(H)— 0 I CF₃O H H ═C(H)— 0 Me CF₃O H H═C(H)— 0 Et CF₃O H H ═C(H)— 0 Pr CF₃O H H ═C(H)— 0 MeO CF₃O H H ═C(H)— 0EtO CF₃O H H ═C(H)— 0 PrO CF₃O H H ═C(H)— 0 CF₃CH₂O CF₃O H H ═C(H)— 0iPrO CF₃O H H ═C(H)— 0 MeS CF₃O H H ═C(H)— 0 EtS CF₃O H H ═C(H)— 0 PrSCF₃O H H ═C(H)— 0 CF₃CH₂S CF₃O H H ═C(H)— 0 iPrS CF₃O H H ═C(H)— 0 PhCF₃O H H ═C(H)— 0 2-Py CF₃O H H ═C(H)— 0

TABLE 9 R³ R⁵ R⁶ R⁷ A² n 3-Py CF₃O H H ═C(H)— 0 4-Py CF₃O H H ═C(H)— 01-Tz CF₃O H H ═C(H)— 0 1-Pz CF₃O H H ═C(H)— 0 H CF₃O H H ═C(H)— 1 ClCF₃O H H ═C(H)— 1 Br CF₃O H H ═C(H)— 1 I CF₃O H H ═C(H)— 1 Me CF₃O H H═C(H)— 1 Et CF₃O H H ═C(H)— 1 Pr CF₃O H H ═C(H)— 1 MeO CF₃O H H ═C(H)— 1EtO CF₃O H H ═C(H)— 1 PrO CF₃O H H ═C(H)— 1 CF₃CH₂O CF₃O H H ═C(H)— IiPrO CF₃O H H ═C(H)— 1 Ph CF₃O H H ═C(H)— 1 H CF₃S H H ═C(H)— 0 F CF₃S HH ═C(H)— 0 Cl CF₃S H H ═C(H)— 0 Br CF₃S H H ═C(H)— 0 I CF₃S H H ═C(H)— 0Me CF₃S H H ═C(H)— 0 Et CF₃S H H ═C(H)— 0

TABLE 10 R³ R⁵ R⁶ R⁷ A² n Pr CF₃S H H ═C(H)— 0 MeO CF₃S H H ═C(H)— 0 EtOCF₃S H H ═C(H)— 0 PrO CF₃S H H ═C(H)— 0 CF₃CH₂O CF₃S H H ═C(H)— 0 iPrOCF₃S H H ═C(H)— 0 MeS CF₃S H H ═C(H)— 0 EtS CF₃S H H ═C(H)— 0 PrS CF₃S HH ═C(H)— 0 CF₃CH₂S CF₃S H H ═C(H)— 0 iPrS CF₃S H H ═C(H)— 0 Ph CF₃S H H═C(H)— 0 2-Py CF₃S H H ═C(H)— 0 3-Py CF₃S H H ═C(H)— 0 4-Py CF₃S H H═C(H)— 0 1-Tz CF₃S H H ═C(H)— 0 1-Pz CF₃S H H ═C(H)— 0 H H tBu H ═C(H)—0 F H tBu H ═C(H)— 0 Cl H tBu H ═C(H)— 0 Br H tBu H ═C(H)— 0 I H tBu H═C(H)— 0 Me H tBu H ═C(H)— 0 Et H tBu H ═C(H)— 0

TABLE 11 R³ R⁵ R⁶ R⁷ A² n Pr H tBu H ═C(H)— 0 MeO H tBu H ═C(H)— 0 EtO HtBu H ═C(H)— 0 PrO H tBu H ═C(H)— 0 CF₃CH₂O H tBu H ═C(H)— 0 iPrO H tBuH ═C(H)— 0 MeS H tBu H ═C(H)— 0 EtS H tBu H ═C(H)— 0 PrS H tBu H ═C(H)—0 CF₃CH₂S H tBu H ═C(H)— 0 iPrS H tBu H ═C(H)— 0 Ph H tBu H ═C(H)— 02-Py H tBu H ═C(H)— 0 3-Py H tBu H ═C(H)— 0 4-Py H tBu H ═C(H)— 0 1-Tz HtBu H ═C(H)— 0 1-Pz H tBu H ═C(H)— 0 H H tBu H ═C(H)— 1 Cl H tBu H═C(H)— 1 Br H tBu H ═C(H)— 1 I H tBu H ═C(H)— 1 Me H tBu H ═C(H)— 1 Et HtBu H ═C(H)— 1 Pr H tBu H ═C(H)— 1

TABLE 12 R³ R⁵ R⁶ R⁷ A² n MeO H tBu H ═C(H)— 1 EtO H tBu H ═C(H)— 1 PrOH tBu H ═C(H)— 1 CF₃CH₂O H tBu H ═C(H)— 1 iPrO H tBu H ═C(H)— 1 Ph H tBuH ═C(H)— 1 H H CF₃ H ═C(H)— 0 F H CF₃ H ═C(H)— 0 Cl H CF₃ H ═C(H)— 0 BrH CF₃ H ═C(H)— 0 I H CF₃ H ═C(H)— 0 Me H CF₃ H ═C(H)— 0 Et H CF₃ H═C(H)— 0 Pr H CF₃ H ═C(H)— 0 MeO H CF₃ H ═C(H)— 0 EtO H CF₃ H ═C(H)— 0PrO H CF₃ H ═C(H)— 0 CF₃CH₂O H CF₃ H ═C(H)— 0 iPrO H CF₃ H ═C(H)— 0 MeSH CF₃ H ═C(H)— 0 EtS H CF₃ H ═C(H)— 0 PrS H CF₃ H ═C(H)— 0 CF₃CH₂S H CF₃H ═C(H)— 0 iPrS H CF₃ H ═C(H)— 0

TABLE 13 R³ R⁵ R⁶ R⁷ A² n Ph H CF₃ H ═C(H)— 0 2-Py H CF₃ H ═C(H)— 0 3-PyH CF₃ H ═C(H)— 0 4-Py H CF₃ H ═C(H)— 0 1-Tz H CF₃ H ═C(H)— 0 1-Pz H CF₃H ═C(H)— 0 H H CF₃ H ═C(H)— 1 Cl H CF₃ H ═C(H)— 1 Br H CF₃ H ═C(H)— 1 IH CF₃ H ═C(H)— 1 Me H CF₃ H ═C(H)— 1 Et H CF₃ H ═C(H)— 1 Pr H CF₃ H═C(H)— 1 MeO H CF₃ H ═C(H)— 1 EtO H CF₃ H ═C(H)— 1 PrO H CF₃ H ═C(H)— 1CF₃CH₂O H CF₃ H ═C(H)— 1 iPrO H CF₃ H ═C(H)— 1 Ph H CF₃ H ═C(H)— 1 H ClCF₃ H ═C(H)— 0 F Cl CF₃ H ═C(H)— 0 Cl Cl CF₃ H ═C(H)— 0 Br Cl CF₃ H═C(H)— 0 I Cl CF₃ H ═C(H)— 0

TABLE 14 R³ R⁵ R⁶ R⁷ A² n Me Cl CF₃ H ═C(H)— 0 Et Cl CF₃ H ═C(H)— 0 PrCl CF₃ H ═C(H)— 0 MeO Cl CF₃ H ═C(H)— 0 EtO Cl CF₃ H ═C(H)— 0 PrO Cl CF₃H ═C(H)— 0 CF₃CH₂O Cl CF₃ H ═C(H)— 0 iPrO Cl CF₃ H ═C(H)— 0 MeS CI CF₃ H═C(H)— 0 EtS Cl CF₃ H ═C(H)— 0 PrS Cl CF₃ H ═C(H)— 0 CF₃CH₂S Cl CF₃ H═C(H)— 0 iPrS Cl CF₃ H ═C(H)— 0 Ph Cl CF₃ H ═C(H)— 0 2-Py Cl CF₃ H═C(H)— 0 3-Py Cl CF₃ H ═C(H)— 0 4-Py Cl CF₃ H ═C(H)— 0 1-Tz Cl CF₃ H═C(H)— 0 1-Pz Cl CF₃ H ═C(H)— 0 H Cl CF₃ H ═C(H)— 1 Cl Cl CF₃ H ═C(H)— 1Br Cl CF₃ H ═C(H)— 1 I Cl CF₃ H ═C(H)— 1 Me Cl CF₃ H ═C(H)— I

TABLE 15 R³ R⁵ R⁶ R⁷ A² n Et Cl CF₃ H ═C(H)— 1 Pr Cl CF₃ H ═C(H)— 1 MeOCl CF₃ H ═C(H)— 1 EtO Cl CF₃ H ═C(H)— 1 PrO Cl CF₃ H ═C(H)— 1 CF₃CH₂O ClCF₃ H ═C(H)— 1 iPrO Cl CF₃ H ═C(H)— 1 Ph Cl CF₃ H ═C(H)— 1 H H CF₃ Cl═C(H)— 0 F H CF₃ Cl ═C(H)— 0 Cl H CF₃ Cl ═C(H)— 0 Br H CF₃ Cl ═C(H)— 0 IH CF₃ Cl ═C(H)— 0 Me H CF₃ Cl ═C(H)— 0 Et H CF₃ Cl ═C(H)— 0 Pr H CF₃ Cl═C(H)— 0 MeO H CF₃ Cl ═C(H)— 0 EtO H CF₃ Cl ═C(H)— 0 PrO H CF₃ Cl ═C(H)—0 CF₃CH₂O H CF₃ Cl ═C(H)— 0 iPrO H CF₃ Cl ═C(H)— 0 MeS H CF₃ Cl ═C(H)— 0EtS H CF₃ Cl ═C(H)— 0 PrS H CF₃ Cl ═C(H)— 0

TABLE 16 R³ R⁵ R⁶ R⁷ A² n CF₃CH₂S H CF₃ Cl ═C(H)— 0 iPrS H CF₃ Cl ═C(H)—0 Ph H CF₃ Cl ═C(H)— 0 2-Py H CF₃ Cl ═C(H)— 0 3-Py H CF₃ Cl ═C(H)— 04-Py H CF₃ Cl ═C(H)— 0 1-Tz H CF₃ Cl ═C(H)— 0 1-Pz H CF₃ Cl ═C(H)— 0 H HCF₃ Cl ═C(H)— 1 Cl H CF₃ Cl ═C(H)— 1 Br H CF₃ Cl ═C(H)— 1 I H CF₃ Cl═C(H)— 1 Me H CF₃ Cl ═C(H)— 1 Et H CF₃ Cl ═C(H)— 1 Pr H CF₃ Cl ═C(H)— 1MeO H CF₃ Cl ═C(H)— 1 EtO H CF₃ Cl ═C(H)— 1 PrO H CF₃ Cl ═C(H)— 1CF₃CH₂O H CF₃O H ═C(H)— 1 iPrO H CF₃O H ═C(H)— 1 Ph H CF₃O H ═C(H)— 1 HH CF₃O H ═C(H)— 0 F H CF₃O H ═C(H)— 0 Cl H CF₃O H ═C(H)— 0

TABLE 17 R³ R⁵ R⁶ R⁷ A² n Br H CF₃O H ═C(H)— 0 I H CF₃O H ═C(H)— 0 Me HCF₃O H ═C(H)— 0 Et H CF₃O H ═C(H)— 0 Pr H CF₃O H ═C(H)— 0 MeO H CF₃O H═C(H)— 0 EtO H CF₃O H ═C(H)— 0 PrO H CF₃O H ═C(H)— 0 CF₃CH₂O H CF₃O H═C(H)— 0 iPrO H CF₃O H ═C(H)— 0 MeS H CF₃O H ═C(H)— 0 EtS H CF₃O H═C(H)— 0 PrS H CF₃O H ═C(H)— 0 CF₃CH₂S H CF₃O H ═C(H)— 0 iPrS H CF₃O H═C(H)— 0 Ph H CF₃O H ═C(H)— 0 2-Py H CF₃O H ═C(H)— 0 3-Py H CF₃O H═C(H)— 0 4-Py H CF₃O H ═C(H)— 0 1-Tz H CF₃O H ═C(H)— 0 1-Pz H CF₃O H═C(H)— 0 H H CF₃O H ═C(H)— 1 Cl H CF₃O H ═C(H)— 1 Br H CF₃O H ═C(H)— 1

TABLE 18 R³ R⁵ R⁶ R⁷ A² n I H CF₃O H ═C(H)— 1 Me H CF₃O H ═C(H)— 1 Et HCF₃O H ═C(H)— 1 Pr H CF₃O H ═C(H)— 1 MeO H CF₃O H ═C(H)— 1 EtO H CF₃O H═C(H)— 1 PrO H CF₃O H ═C(H)— 1 CF₃CH₂O H CF₃O H ═C(H)— 1 iPrO H CF₃O H═C(H)— 1 Ph H CF₃O H ═C(H)— 1 H H CF₃S H ═C(H)— 0 F H CF₃S H ═C(H)— 0 ClH CF₃S H ═C(H)— 0 Br H CF₃S H ═C(H)— 0 I H CF₃S H ═C(H)— 0 Me H CF₃S H═C(H)— 0 Et H CF₃S H ═C(H)— 0 Pr H CF₃S H ═C(H)— 0 MeO H CF₃S H ═C(H)— 0EtO H CF₃S H ═C(H)— 0 PrO H CF₃S H ═C(H)— 0 CF₃CH₂O H CF₃S H ═C(H)— 0iPrO H CF₃S H ═C(H)— 0 MeS H CF₃S H ═C(H)— 0

TABLE 19 R³ R⁵ R⁶ R⁷ A² n EtS H CF₃S H ═C(H)— 0 PrS H CF₃S H ═C(H)— 0CF₃CH₂S H CF₃S H ═C(H)— 0 iPrS H CF₃S H ═C(H)— 0 Ph H CF₃S H ═C(H)— 02-Py H CF₃S H ═C(H)— 0 3-Py H CF₃S H ═C(H)— 0 4-Py H CF₃S H ═C(H)— 01-Tz H CF₃S H ═C(H)— 0 1-Pz H CF₃S H ═C(H)— 0 H —CF₂OCF₂— H ═C(H)— 0 F—CF₂OCF₂— H ═C(H)— 0 Cl —CF₂OCF₂— H ═C(H)— 0 Br —CF₂OCF₂— H ═C(H)— 0 I—CF₂OCF₂— H ═C(H)— 0 Me —CF₂OCF₂— H ═C(H)— 0 Et —CF₂OCF₂— H ═C(H)— 0 Pr—CF₂OCF₂— H ═C(H)— 0 MeO —CF₂OCF₂— H ═C(H)— 0 EtO —CF₂OCF₂— H ═C(H)— 0PrO —CF₂OCF₂— H ═C(H)— 0 CF₃CH₂O —CF₂OCF₂— H ═C(H)— 0 iPrO —CF₂OCF₂— H═C(H)— 0 MeS —CF₂OCF₂— H ═C(H)— 0

TABLE 20 R³ R⁵ R⁶ R⁷ A² n EtS —CF₂OCF₂— H ═C(H)— 0 PrS —CF₂OCF₂— H═C(H)— 0 CF₃CH₂S —CF₂OCF₂— H ═C(H)— 0 iPrS —CF₂OCF₂— H ═C(H)— 0 Ph—CF₂OCF₂— H ═C(H)— 0 2-Py —CF₂OCF₂— H ═C(H)— 0 3-Py —CF₂OCF₂— H ═C(H)— 04-Py —CF₂OCF₂— H ═C(H)— 0 1-Tz —CF₂OCF₂— H ═C(H)— 0 1-Pz —CF₂OCF₂— H═C(H)— 0 H —CF₂OCF₂— H ═C(H)— 1 Cl —CF₂OCF₂— H ═C(H)— 1 Br —CF₂OCF₂— H═C(H)— 1 I —CF₂OCF₂— H ═C(H)— 1 Me —CF₂OCF₂— H ═C(H)— 1 Et —CF₂OCF₂— H═C(H)— 1 Pr —CF₂OCF₂— H ═C(H)— 1 MeO —CF₂OCF₂— H ═C(H)— 1 EtO —CF₂OCF₂—H ═C(H)— 1 PrO —CF₂OCF₂— H ═C(H)— 1 CF₃CH₂O —CF₂OCF₂— H ═C(H)— 1 iPrO—CF₂OCF₂— H ═C(H)— 1 Ph —CF₂OCF₂— H ═C(H)— 1 H —CF₂CH₂CH₂— H ═C(H)— 0

TABLE 21 R³ R⁵ R⁶ R⁷ A² n F —CF₂CH₂CH₂— H ═C(H)— 0 Cl —CF₂CH₂CH₂— H═C(H)— 0 Br —CF₂CH₂CH₂— H ═C(H)— 0 I —CF₂CH₂CH₂— H ═C(H)— 0 Me—CF₂CH₂CH₂— H ═C(H)— 0 Et —CF₂CH₂CH₂— H ═C(H)— 0 Pr —CF₂CH₂CH₂— H ═C(H)—0 MeO —CF₂CH₂CH₂— H ═C(H)— 0 EtO —CF₂CH₂CH₂— H ═C(H)— 0 PrO —CF₂CH₂CH₂—H ═C(H)— 0 CF₃CH₂O —CF₂CH₂CH₂— H ═C(H)— 0 iPrO —CF₂CH₂CH₂— H ═C(H)— 0MeS —CF₂CH₂CH₂— H ═C(H)— 0 EtS —CF₂CH₂CH₂— H ═C(H)— 0 PrS —CF₂CH₂CH₂— H═C(H)— 0 CF₃CH₂S —CF₂CH₂CH₂— H ═C(H)— 0 iPrS —CF₂CH₂CH₂— H ═C(H)— 0 Ph—CF₂CH₂CH₂— H ═C(H)— 0 2-Py —CF₂CH₂CH₂— H ═C(H)— 0 3-Py —CF₂CH₂CH₂— H═C(H)— 0 4-Py —CF₂CH₂CH₂— H ═C(H)— 0 1-Tz —CF₂CH₂CH₂— H ═C(H)— 0 1-Pz—CF₂CH₂CH₂— H ═C(H)— 0 H —CF₂CH₂O— H ═C(H)— 0

TABLE 22 R³ R⁵ R⁶ R⁷ A² n F —CF₂CH₂O— H ═C(H)— 0 Cl —CF₂CH₂O— H ═C(H)— 0Br —CF₂CH₂O— H ═C(H)— 0 I —CF₂CH₂O— H ═C(H)— 0 Me —CF₂CH₂O— H ═C(H)— 0Et —CF₂CH₂O— H ═C(H)— 0 Pr —CF₂CH₂O— H ═C(H)— 0 MeO —CF₂CH₂O— H ═C(H)— 0EtO —CF₂CH₂O— H ═C(H)— 0 PrO —CF₂CH₂O— H ═C(H)— 0 CF₃CH₂O —CF₂CH₂O— H═C(H)— 0 iPrO —CF₂CH₂O— H ═C(H)— 0 MeS —CF₂CH₂O— H ═C(H)— 0 EtS—CF₂CH₂O— H ═C(H)— 0 PrS —CF₂CH₂O— H ═C(H)— 0 CF₃CH₂S —CF₂CH₂O— H ═C(H)—0 iPrS —CF₂CH₂O— H ═C(H)— 0 Ph —CF₂CH₂O— H ═C(H)— 0 2-Py —CF₂CH₂O— H═C(H)— 0 3-Py —CF₂CH₂O— H ═C(H)— 0 4-Py —CF₂CH₂O— H ═C(H)— 0 1-Tz—CF₂CH₂O— H ═C(H)— 0 1-Pz —CF₂CH₂O— H ═C(H)— 0 H —CH₂CH₂CF₂— H ═C(H)— 0

TABLE 23 R³ R⁵ R⁶ R⁷ A² n F —CH₂CH₂CF₂— H ═C(H)— 0 Cl —CH₂CH₂CF₂— H═C(H)— 0 Br —CH₂CH₂CF₂— H ═C(H)— 0 I —CH₂CH₂CF₂— H ═C(H)— 0 Me—CH₂CH₂CF₂— H ═C(H)— 0 Et —CH₂CH₂CF₂— H ═C(H)— 0 Pr —CH₂CH₂CF₂— H ═C(H)—0 MeO —CH₂CH₂CF₂— H ═C(H)— 0 EtO —CH₂CH₂CF₂— H ═C(H)— 0 PrO —CH₂CH₂CF₂—H ═C(H)— 0 CF₃CH₂O —CH₂CH₂CF₂— H ═C(H)— 0 iPrO —CH₂CH₂CF₂— H ═C(H)— 0MeS —CH₂CH₂CF₂— H ═C(H)— 0 EtS —CH₂CH₂CF₂— H ═C(H)— 0 PrS —CH₂CH₂CF₂— H═C(H)— 0 CF₃CH₂S —CH₂CH₂CF₂— H ═C(H)— 0 iPrS —CH₂CH₂CF₂— H ═C(H)— 0 Ph—CH₂CH₂CF₂— H ═C(H)— 0 2-Py —CH₂CH₂CF₂— H ═C(H)— 0 3-Py —CH₂CH₂CF₂— H═C(H)— 0 4-Py —CH₂CH₂CF₂— H ═C(H)— 0 1-Tz —CH₂CH₂CF₂— H ═C(H)— 0 1-Pz—CH₂CH₂CF₂— H ═C(H)— 0 H —CF₂CH₂CH₂CH₂— H ═C(H)— 0

TABLE 24 R³ R⁵ R⁶ R⁷ A² n F —CF₂CH₂CH₂CH₂— H ═C(H)— 0 Cl —CF₂CH₂CH₂CH₂—H ═C(H)— 0 Br —CF₂CH₂CH₂CH₂— H ═C(H)— 0 I —CF₂CH₂CH₂CH₂— H ═C(H)— 0 Me—CF₂CH₂CH₂CH₂— H ═C(H)— 0 Et —CF₂CH₂CH₂CH₂— H ═C(H)— 0 Pr —CF₂CH₂CH₂CH₂—H ═C(H)— 0 MeO —CF₂CH₂CH₂CH₂— H ═C(H)— 0 EtO —CF₂CH₂CH₂CH₂— H ═C(H)— 0PrO —CF₂CH₂CH₂CH₂— H ═C(H)— 0 CF₃CH₂O —CF₂CH₂CH₂CH₂— H ═C(H)— 0 iPrO—CF₂CH₂CH₂CH₂— H ═C(H)— 0 MeS —CF₂CH₂CH₂CH₂— H ═C(H)— 0 EtS—CF₂CH₂CH₂CH₂— H ═C(H)— 0 PrS —CF₂CH₂CH₂CH₂— H ═C(H)— 0 CF₃CH₂S—CF₂CH₂CH₂CH₂— H ═C(H)— 0 iPrS —CF₂CH₂CH₂CH₂— H ═C(H)— 0 Ph—CF₂CH₂CH₂CH₂— H ═C(H)— 0 2-Py —CF₂CH₂CH₂CH₂— H ═C(H)— 0 3-Py—CF₂CH₂CH₂CH₂— H ═C(H)— 0 4-Py —CF₂CH₂CH₂CH₂— H ═C(H)— 0 1-Tz—CF₂CH₂CH₂CH₂— H ═C(H)— 0 1-Pz —CF₂CH₂CH₂CH₂— H ═C(H)— 0 H —CF₂CH₂CH₂O—H ═C(H)— 0

TABLE 25 R³ R⁵ R⁶ R⁷ A² n F —CF₂CH₂CH₂O— H ═C(H)— 0 Cl —CF₂CH₂CH₂O— H═C(H)— 0 Br —CF₂CH₂CH₂O— H ═C(H)— 0 I —CF₂CH₂CH₂O— H ═C(H)— 0 Me—CF₂CH₂CH₂O— H ═C(H)— 0 Et —CF₂CH₂CH₂O— H ═C(H)— 0 Pr —CF₂CH₂CH₂O— H═C(H)— 0 MeO —CF₂CH₂CH₂O— H ═C(H)— 0 EtO —CF₂CH₂CH₂O— H ═C(H)— 0 PrO—CF₂CH₂CH₂O— H ═C(H)— 0 CF₃CH₂O —CF₂CH₂CH₂O— H ═C(H)— 0 iPrO—CF₂CH₂CH₂O— H ═C(H)— 0 MeS —CF₂CH₂CH₂O— H ═C(H)— 0 EtS —CF₂CH₂CH₂O— H═C(H)— 0 PrS —CF₂CH₂CH₂O— H ═C(H)— 0 CF₃CH₂S —CF₂CH₂CH₂O— H ═C(H)— 0iPrS —CF₂CH₂CH₂O— H ═C(H)— 0 Ph —CF₂CH₂CH₂O— H ═C(H)— 0 2-Py—CF₂CH₂CH₂O— H ═C(H)— 0 3-Py —CF₂CH₂CH₂O— H ═C(H)— 0 4-Py —CF₂CH₂CH₂O— H═C(H)— 0 1-Tz —CF₂CH₂CH₂O— H ═C(H)— 0 1-Pz —CF₂CH₂CH₂O— H ═C(H)— 0 H—CH₂CH₂CH₂CF₂— H ═C(H)— 0

R³ R⁵ R⁶ R⁷ A² n F —CH₂CH₂CH₂CF₂— H ═C(H)— 0 Cl —CH₂CH₂CH₂CF₂— H ═C(H)—0 Br —CH₂CH₂CH₂CF₂— H ═C(H)— 0 I —CH₂CH₂CH₂CF₂— H ═C(H)— 0 Me—CH₂CH₂CH₂CF₂— H ═C(H)— 0 Et —CH₂CH₂CH₂CF₂— H ═C(H)— 0 Pr —CH₂CH₂CH₂CF₂—H ═C(H)— 0 MeO —CH₂CH₂CH₂CF₂— H ═C(H)— 0 EtO —CH₂CH₂CH₂CF₂— H ═C(H)— 0PrO —CH₂CH₂CH₂CF₂— H ═C(H)— 0 CF₃CH₂O —CH₂CH₂CH₂CF₂— H ═C(H)— 0 iPrO—CH₂CH₂CH₂CF₂— H ═C(H)— 0 MeS —CH₂CH₂CH₂CF₂— H ═C(H)— 0 EtS—CH₂CH₂CH₂CF₂— H ═C(H)— 0 PrS —CH₂CH₂CH₂CF₂— H ═C(H)— 0 CF₃CH₂S—CH₂CH₂CH₂CF₂— H ═C(H)— 0 iPrS —CH₂CH₂CH₂CF₂— H ═C(H)— 0 Ph—CH₂CH₂CH₂CF₂— H ═C(H)— 0 2-Py —CH₂CH₂CH₂CF₂— H ═C(H)— 0 3-Py—CH₂CH₂CH₂CF₂— H ═C(H)— 0 4-Py —CH₂CH₂CH₂CF₂— H ═C(H)— 0 1-Tz—CH₂CH₂CH₂CF₂— H ═C(H)— 0 1-Pz —CH₂CH₂CH₂CF₂— H ═C(H)— 0 H —OCH₂CH₂CF₂—H ═C(H)— 0

TABLE 27 R³ R⁵ R⁶ R⁷ A² n F —OCH₂CH₂CF₂— H ═C(H)— 0 Cl —OCH₂CH₂CF₂— H═C(H)— 0 Br —OCH₂CH₂CF₂— H ═C(H)— 0 I —OCH₂CH₂CF₂— H ═C(H)— 0 Me—OCH₂CH₂CF₂— H ═C(H)— 0 Et —OCH₂CH₂CF₂— H ═C(H)— 0 Pr —OCH₂CH₂CF₂— H═C(H)— 0 MeO —OCH₂CH₂CF₂— H ═C(H)— 0 EtO —OCH₂CH₂CF₂— H ═C(H)— 0 PrO—OCH₂CH₂CF₂— H ═C(H)— 0 CF₃CH₂O —OCH₂CH₂CF₂— H ═C(H)— 0 iPrO—OCH₂CH₂CF₂— H ═C(H)— 0 MeS —OCH₂CH₂CF₂— H ═C(H)— 0 EtS —OCH₂CH₂CF₂— H═C(H)— 0 PrS —OCH₂CH₂CF₂— H ═C(H)— 0 CF₃CH₂S —OCH₂CH₂CF₂— H ═C(H)— 0iPrS —OCH₂CH₂CF₂— H ═C(H)— 0 Ph —OCH₂CH₂CF₂— H ═C(H)— 0 2-Py—OCH₂CH₂CF₂— H ═C(H)— 0 3-Py —OCH₂CH₂CF₂— H ═C(H)— 0 4-Py —OCH₂CH₂CF₂— H═C(H)— 0 1-Tz —OCH₂CH₂CF₂— H ═C(H)— 0 1-Pz —OCH₂CH₂CF₂— H ═C(H)— 0

TABLE 28 R³ R⁵ R⁶ R⁷ A² n CH₃OCH₂ tBu H H ═C(H)— 0 CHF₂CH₂O tBu H H═C(H)— 0 MeS(O) tBu H H ═C(H)— 0 MeS(O)₂ tBu H H ═C(H)— 0 EtS(O) tBu H H═C(H)— 0 EtS(O)₂ tBu H H ═C(H)— 0 PrS(O) tBu H H ═C(H)— 0 PrS(O)₂ tBu HH ═C(H)— 0 CHF₂CH₂S tBu H H ═C(H)— 0 iPrS(O) tBu H H ═C(H)— 0 iPrS(O)₂tBu H H ═C(H)— 0 CF₃ tBu H H ═C(H)— 0 CH₃OCH₂ CF₃ H H ═C(H)— 0 CHF₂CH₂OCF₃ H H ═C(H)— 0 MeS(O) CF₃ H H ═C(H)— 0 MeS(O)₂ CF₃ H H ═C(H)— 0 EtS(O)CF₃ H H ═C(H)— 0 EtS(O)₂ CF₃ H H ═C(H)— 0 PrS(O) CF₃ H H ═C(H)— 0PrS(O)₂ CF₃ H H ═C(H)— 0 CHF₂CH₂S CF₃ H H ═C(H)— 0 iPrS(O) CF₃ H H═C(H)— 0 iPrS(O)₂ CF₃ H H ═C(H)— 0 CF₃ CF₃ H H ═C(H)— 0

TABLE 29 R³ R⁵ R⁶ R⁷ A² n CH₃OCH₂ CF₃O H H ═C(H)— 0 CHF₂CH₂O CF₃O H H═C(H)— 0 MeS(O) CF₃O H H ═C(H)— 0 MeS(O)₂ CF₃O H H ═C(H)— 0 EtS(O) CF₃OH H ═C(H)— 0 EtS(O)₂ CF₃O H H ═C(H)— 0 PrS(O) CF₃O H H ═C(H)— 0 PrS(O)₂CF₃O H H ═C(H)— 0 CHF₂CH₂S CF₃O H H ═C(H)— 0 iPrS(O) CF₃O H H ═C(H)— 0iPrS(O)₂ CF₃O H H ═C(H)— 0 CF₃ CF₃O H H ═C(H)— 0 CH₃OCH₂ CF₃ H H ═N— 0CHF₂CH₂O CF₃ H H ═N— 0 MeS(O) CF₃ H H ═N— 0 MeS(O)₂ CF₃ H H ═N— 0 EtS(O)CF₃ H H ═N— 0 EtS(O)₂ CF₃ H H ═N— 0 PrS(O) CF₃ H H ═N— 0 PrS(O)₂ CF₃ H H═N— 0 CHF₂CH₂S CF₃ H H ═N— 0 iPrS(O) CF₃ H H ═N— 0 iPrS(O)₂ CF₃ H H ═N—0 CF₃ CF₃ H H ═N— 0

TABLE 30 R³ R⁵ R⁶ R⁷ A² n CH₃OCH₂ H tBu H ═C(H)— 0 CHF₂CH₂O H tBu H═C(H)— 0 MeS(O) H tBu H ═C(H)— 0 MeS(O)₂ H tBu H ═C(H)— 0 EtS(O) H tBu H═C(H)— 0 EtS(O)₂ H tBu H ═C(H)— 0 PrS(O) H tBu H ═C(H)— 0 PrS(O)₂ H tBuH ═C(H)— 0 CHF₂CH₂S H tBu H ═C(H)— 0 iPrS(O) H tBu H ═C(H)— 0 iPrS(O)₂ HtBu H ═C(H)— 0 CF₃ H tBu H ═C(H)— 0 CH₃OCH₂ H CF₃ H ═C(H)— 0 CHF₂CH₂O HCF₃ H ═C(H)— 0 MeS(O) H CF₃ H ═C(H)— 0 MeS(O)₂ H CF₃ H ═C(H)— 0 EtS(O) HCF₃ H ═C(H)— 0 EtS(O)₂ H CF₃ H ═C(H)— 0 PrS(O) H CF₃ H ═C(H)— 0 PrS(O)₂H CF₃ H ═C(H)— 0 CHF₂CH₂S H CF₃ H ═C(H)— 0 iPrS(O) H CF₃ H ═C(H)— 0iPrS(O)₂ H CF₃ H ═C(H)— 0 CF₃ H CF₃ H ═C(H)— 0

TABLE 31 R³ R⁵ R⁶ R⁷ A² n CH₃OCH₂ H CF₃O H ═C(H)— 0 CHF₂CH₂O H CF₃O H═C(H)— 0 MeS(O) H CF₃O H ═C(H)— 0 MeS(O)₂ H CF₃O H ═C(H)— 0 EtS(O) HCF₃O H ═C(H)— 0 EtS(O)₂ H CF₃O H ═C(H)— 0 PrS(O) H CF₃O H ═C(H)— 0PrS(O)₂ H CF₃O H ═C(H)— 0 CHF₂CH₂S H CF₃O H ═C(H)— 0 iPrS(O) H CF₃O H═C(H)— 0 iPrS(O)₂ H CF₃O H ═C(H)— 0 CF₃ H CF₃O H ═C(H)— 0 CH₃OCH₂ tBu HH ═N— 0 CHF₂CH₂O tBu H H ═N— 0 MeS(O) tBu H H ═N— 0 MeS(O)₂ tBu H H ═N—0 EtS(O) tBu H H ═N— 0 EtS(O)₂ tBu H H ═N— 0 PrS(O) tBu H H ═N— 0PrS(O)₂ tBu H H ═N— 0 CHF₂CH₂S tBu H H ═N— 0 iPrS(O) tBu H H ═N— 0iPrS(O)₂ tBu H H ═N— 0 CF₃ tBu H H ═N— 0

TABLE 32 R³ R⁵ R⁶ R⁷ A² n H tBu H H ═N— 0 F tBu H H ═N— 0 Cl tBu H H ═N—0 Br tBu H H ═N— 0 I tBu H H ═N— 0 Me tBu H H ═N— 0 Et tBu H H ═N— 0 PrtBu H H ═N— 0 MeO tBu H H ═N— 0 EtO tBu H H ═N— 0 PrO tBu H H ═N— 0CF₃CH₂O tButBu H H ═N— 0 iPrO tBu H H ═N— 0 MeS tBu H H ═N— 0 EtS tBu HH ═N— 0 PrS tBu H H ═N— 0 CF₃CH₂S tBu H H ═N— 0 iPrS tBu H H ═N— 0CH₃OCH₂ —CF₂OCF₂— H ═C(H)— 0 CHF₂CH₂O —CF₂OCF₂— H ═C(H)— 0 MeS(O)—CF₂OCF₂— H ═C(H)— 0 MeS(O)₂ —CF₂OCF₂— H ═C(H)— 0 EtS(O) —CF₂OCF₂— H═C(H)— 0 EtS(O)₂ —CF₂OCF₂— H ═C(H)— 0

TABLE 33 R³ R⁵ R⁶ R⁷ A² n PrS(O) —CF₂OCF₂— H ═C(H)— 0 PrS(O)₂ —CF₂OCF₂—H ═C(H)— 0 CHF₂CH₂S —CF₂OCF₂— H ═C(H)— 0 iPrS(O) —CF₂OCF₂— H ═C(H)— 0iPrS(O)₂ —CF₂OCF₂— H ═C(H)— 0 CF₃ —CF₂OCF₂— H ═C(H)— 0 H —OC(CH₃)₂CH₂— H═C(H)— 0 F —OC(CH₃)₂CH₂— H ═C(H)— 0 Cl —OC(CH₃)₂CH₂— H ═C(H)— 0 Br—OC(CH₃)₂CH₂— H ═C(H)— 0 I —OC(CH₃)₂CH₂— H ═C(H)— 0 Me —OC(CH₃)₂CH₂— H═C(H)— 0 Et —OC(CH₃)₂CH₂— H ═C(H)— 0 Pr —OC(CH₃)₂CH₂— H ═C(H)— 0 CH₃OCH₂—OC(CH₃)₂CH₂— H ═C(H)— 0 MeO —OC(CH₃)₂CH₂— H ═C(H)— 0 EtO —OC(CH₃)₂CH₂—H ═C(H)— 0 PrO —OC(CH₃)₂CH₂— H ═C(H)— 0 CHF₂CH₂O —OC(CH₃)₂CH₂— H ═C(H)—0 CF₃CH₂O —OC(CH₃)₂CH₂— H ═C(H)— 0 iPrO —OC(CH₃)₂CH₂— H ═C(H)— 0 MeS—OC(CH₃)₂CH₂— H ═C(H)— 0 MeS(O) —OC(CH₃)₂CH₂— H ═C(H)— 0 MeS(O)₂—OC(CH₃)₂CH₂— H ═C(H)— 0

TABLE 34 R³ R⁵ R⁶ R⁷ A² n EtS —OC(CH₃)₂CH₂— H ═C(H)— 0 EtS(O)—OC(CH₃)₂CH₂— H ═C(H)— 0 EtS(O)₂ —OC(CH₃)₂CH₂— H ═C(H)— 0 PrS—OC(CH₃)₂CH₂— H ═C(H)— 0 PrS(O) —OC(CH₃)₂CH₂— H ═C(H)— 0 PrS(O)₂—OC(CH₃)₂CH₂— H ═C(H)— 0 CHF₂CH₂S —OC(CH₃)₂CH₂— H ═C(H)— 0 CF₃CH₂S—OC(CH₃)₂CH₂— H ═C(H)— 0 iPr —OC(CH₃)₂CH₂— H ═C(H)— 0 iPrS(O)—OC(CH₃)₂CH₂— H ═C(H)— 0 iPrS(O)₂ —OC(CH₃)₂CH₂— H ═C(H)— 0 CF₃—OC(CH₃)₂CH₂— H ═C(H)— 0 H —CH₂C(CH₃)₂O— H ═C(H)— 0 F —CH₂C(CH₃)₂O— H═C(H)— 0 Cl —CH₂C(CH₃)₂O— H ═C(H)— 0 Br —CH₂C(CH₃)₂O— H ═C(H)— 0 I—CH₂C(CH₃)₂O— H ═C(H)— 0 Me —CH₂C(CH₃)₂O— H ═C(H)— 0 Et —CH₂C(CH₃)₂O— H═C(H)— 0 Pr —CH₂C(CH₃)₂O— H ═C(H)— 0 CH₃OCH₂ —CH₂C(CH₃)₂O— H ═C(H)— 0MeO —CH₂C(CH₃)₂O— H ═C(H)— 0 EtO —CH₂C(CH₃)₂O— H ═C(H)— 0 PrO—CH₂C(CH₃)₂O— H ═C(H)— 0

TABLE 35 R³ R⁵ R⁶ R⁷ A² n CHF₂CH₂O —CH₂C(CH₃)₂O— H ═C(H)— 0 CF₃CH₂O—CH₂C(CH₃)₂O— H ═C(H)— 0 iPrO —CH₂C(CH₃)₂O— H ═C(H)— 0 MeS —CH₂C(CH₃)₂O—H ═C(H)— 0 MeS(O) —CH₂C(CH₃)₂O— H ═C(H)— 0 MeS(O)₂ —CH₂C(CH₃)₂O— H═C(H)— 0 EtS —CH₂C(CH₃)₂O— H ═C(H)— 0 EtS(O) —CH₂C(CH₃)₂O— H ═C(H)— 0EtS(O)₂ —CH₂C(CH₃)₂O— H ═C(H)— 0 PrS —CH₂C(CH₃)₂O— H ═C(H)— 0 PrS(O)—CH₂C(CH₃)₂O— H ═C(H)— 0 PrS(O)₂ —CH₂C(CH₃)₂O— H ═C(H)— 0 CHF₂CH₂S—CH₂C(CH₃)₂O— H ═C(H)— 0 CF₃CH₂S —CH₂C(CH₃)₂O— H ═C(H)— 0 iPr—CH₂C(CH₃)₂O— H ═C(H)— 0 iPrS(O) —CH₂C(CH₃)₂O— H ═C(H)— 0 iPrS(O)₂—CH₂C(CH₃)₂O— H ═C(H)— 0 CF₃ —CH₂C(CH₃)₂O— H ═C(H)— 0

The compound represented by the following formula (1-B):

In the above formula (1-B), substituents used for R³, R⁵, R⁶, R⁷, A¹,and n are available in the combinations shown in the following (Table36) to (Table 42).

TABLE 36 R³ R⁵ R⁶ R⁷ A¹ n H CH₃ H H ═N— 0 F CH₃ H H ═N— 0 Cl CH₃ H H ═N—0 Br CH₃ H H ═N— 0 I CH₃ H H ═N— 0 Me CH₃ H H ═N— 0 Et CH₃ H H ═N— 0 PrCH₃ H H ═N— 0 CH₃OCH₂ CH₃ H H ═N— 0 MeO CH₃ H H ═N— 0 EtO CH₃ H H ═N— 0PrO CH₃ H H ═N— 0 CHF₂CH₂O CH₃ H H ═N— 0 CF₃CH₂O CH₃ H H ═N— 0 iPrO CH₃H H ═N— 0 MeS CH₃ H H ═N— 0 MeS(O) CH₃ H H ═N— 0 MeS(O)₂ CH₃ H H ═N— 0EtS CH₃ H H ═N— 0 EtS(O) CH₃ H H ═N— 0 EtS(O)₂ CH₃ H H ═N— 0 PrS CH₃ H H═N— 0 PrS(O) CH₃ H H ═N— 0 PrS(O)₂ CH₃ H H ═N— 0

TABLE 37 R³ R⁵ R⁶ R⁷ A¹ n CHF₂CH₂S CH₃ H H ═N— 0 CF₃CH₂S CH₃ H H ═N— 0iPrS CH₃ H H ═N— 0 iPrS(O) CH₃ H H ═N— 0 iPrS(O)₂ CH₃ H H ═N— 0 CF₃ CH₃H H ═N— 0 H tBu H H ═N— 0 F tBu H H ═N— 0 Cl tBu H H ═N— 0 Br tBu H H═N— 0 I tBu H H ═N— 0 Me tBu H H ═N— 0 Et tBu H H ═N— 0 Pr tBu H H ═N— 0CH₃OCH₂ tBu H H ═N— 0 MeO tBu H H ═N— 0 EtO tBu H H ═N— 0 PrO tBu H H═N— 0 CHF₂CH₂O tBu H H ═N— 0 CF₃CH₂O tBu H H ═N— 0 iPrO tBu H H ═N— 0MeS tBu H H ═N— 0 MeS(O) tBu H H ═N— 0 MeS(O)₂ tBu H H ═N— 0

TABLE 38 R³ R⁵ R⁶ R⁷ A¹ n EtS tBu H H ═N— 0 EtS(O) tBu H H ═N— 0 EtS(O)₂tBu H H ═N— 0 PrS tBu H H ═N— 0 PrS(O) tBu H H ═N— 0 PrS(O)₂ tBu H H ═N—0 CHF₂CH₂S tBu H H ═N— 0 CF₃CH₂S tBu H H ═N— 0 iPrS tBu H H ═N— 0iPrS(O) tBu H H ═N— 0 iPrS(O)₂ tBu H H ═N— 0 CF₃ tBu H H ═N— 0 H CF₃ H H═N— 0 F CF₃ H H ═N— 0 Cl CF₃ H H ═N— 0 Br CF₃ H H ═N— 0 I CF₃ H H ═N— 0Me CF₃ H H ═N— 0 Et CF₃ H H ═N— 0 Pr CF₃ H H ═N— 0 CH₃OCH₂ CF₃ H H ═N— 0MeO CF₃ H H ═N— 0 EtO CF₃ H H ═N— 0 PrO CF₃ H H ═N— 0

TABLE 39 R³ R⁵ R⁶ R⁷ A¹ n CHF₂CH₂O CF₃ H H ═N— 0 CF₃CH₂O CF₃ H H ═N— 0iPrO CF₃ H H ═N— 0 MeS CF₃ H H ═N— 0 MeS(O) CF₃ H H ═N— 0 MeS(O)₂ CF₃ HH ═N— 0 EtS CF₃ H H ═N— 0 EtS(O) CF₃ H H ═N— 0 EtS(O)₂ CF₃ H H ═N— 0 PrSCF₃ H H ═N— 0 PrS(O) CF₃ H H ═N— 0 PrS(O)₂ CF₃ H H ═N— 0 CHF₂CH₂S CF₃ HH ═N— 0 CF₃CH₂S CF₃ H H ═N— 0 iPrS CF₃ H H ═N— 0 iPrS(O) CF₃ H H ═N— 0iPrS(O)₂ CF₃ H H ═N— 0 CF₃ CF₃ H H ═N— 0 H H tBu H ═N— 0 F H tBu H ═N— 0Cl H tBu H ═N— 0 Br H tBu H ═N— 0 I H tBu H ═N— 0 Me H tBu H ═N— 0

TABLE 40 R³ R⁵ R⁶ R⁷ A¹ n Et H tBu H ═N— 0 Pr H tBu H ═N— 0 CH₃OCH₂ HtBu H ═N— 0 MeO H tBu H ═N— 0 EtO H tBu H ═N— 0 PrO H tBu H ═N— 0CHF₂CH₂O H tBu H ═N— 0 CF₃CH₂O H tBu H ═N— 0 iPrO H tBu H ═N— 0 MeS HtBu H ═N— 0 MeS(O) H tBu H ═N— 0 MeS(O)₂ H tBu H ═N— 0 EtS H tBu H ═N— 0EtS(O) H tBu H ═N— 0 EtS(O)₂ H tBu H ═N— 0 PrS H tBu H ═N— 0 PrS(O) HtBu H ═N— 0 PrS(O)₂ H tBu H ═N— 0 CHF₂CH₂S H tBu H ═N— 0 CF₃CH₂S H tBu H═N— 0 iPrS H tBu H ═N— 0 iPrS(O) H tBu H ═N— 0 iPrS(O)₂ H tBu H ═N— 0CF₃ H tBu H ═N— 0

TABLE 41 R³ R⁵ R⁶ R⁷ A¹ n H H CF₃ H ═N— 0 F H CF₃ H ═N— 0 Cl H CF₃ H ═N—0 Br H CF₃ H ═N— 0 I H CF₃ H ═N— 0 Me H CF₃ H ═N— 0 Et H CF₃ H ═N— 0 PrH CF₃ H ═N— 0 CH₃OCH₂ H CF₃ H ═N— 0 MeO H CF₃ H ═N— 0 EtO H CF₃ H ═N— 0PrO H CF₃ H ═N— 0 CHF₂CH₂O H CF₃ H ═N— 0 CF₃CH₂O H CF₃ H ═N— 0 iPrO HCF₃ H ═N— 0 MeS H CF₃ H ═N— 0 MeS(O) H CF₃ H ═N— 0 MeS(O)₂ H CF₃ H ═N— 0EtS H CF₃ H ═N— 0 EtS(O) H CF₃ H ═N— 0 EtS(O)₂ H CF₃ H ═N— 0 PrS H CF₃ H═N— 0 PrS(O) H CF₃ H ═N— 0 PrS(O)₂ H CF₃ H ═N— 0

TABLE 42 R³ R⁵ R⁶ R⁷ A¹ n CHF₂CH₂S H CF₃ H ═N— 0 CF₃CH₂S H CF₃ H ═N— 0iPrS H CF₃ H ═N— 0 iPrS(O) H CF₃ H ═N— 0 iPrS(O)₂ H CF₃ H ═N— 0 CF₃ HCF₃ H ═N— 0

The composition of the present invention comprises the present activecompound as an active ingredient.

The composition of the present invention may comprise a single speciesof the present active compound, or two or more species of the presentactive compounds. The composition of the present invention preferablycomprises one or more and three or less species of the present activecompounds.

In general, the composition of the present invention comprises carriersand the like as described later, and they can be a preparation in theform of agrochemicals or animal drugs.

The composition of the present invention can be prepared, for example,as the following formulations according to known methods such asdissolution or dispersion of the present active compound in a suitableliquid carrier, mixing or adsorption of the present active compound withor on a suitable solid carrier or ointment base, or mixing or dispersionof the present active compound with or in a suitable gaseous carrier.

Examples of the formulations include an emulsion, an aqueous liquidagent, a microemulsion, a flowable agent, an oil agent, a wettablepowder, a granulated wettable powder, a powder, a granule, amicrogranule, a seed coating agent, a seed immersing agent, a fumigant,a tablet, a microcapsule, a spray, an aerosol, a carbon dioxidepreparation, heated vaporization agents such as a mosquito coil, anelectric mosquito mat or an electric mosquito liquid, an EW agent, anointment, a toxic bait, a capsule, a pellet, a film, an injection, anembrocation, a resin preparation, and a shampoo.

During the preparation of the present composition, auxiliary agents forformulations such as an emulsifier, a suspending agent, a spreadingagent, a penetrant, a wetting agent, a thickener, a stabilizer, a fixer,a binder, a dispersant, or a colorant may be added, as necessary.

The composition of the present invention generally comprises 0.01% to95% by weight of the present active compound.

Examples of the liquid carrier include: the substances listed in the EPAlist (List Nos. 4A and 4B); water; alcohols (e.g. methyl alcohol, ethylalcohol, n-propyl alcohol, isopropyl alcohol, butyl alcohol, hexylalcohol, benzyl alcohol, ethylene glycol, propylene glycol,phenoxyethanol, etc.); ketones (e.g. acetone, methyl ethyl ketone,methyl isobutyl ketone, cyclohexanone, etc.); ethers (e.g. diisopropylether, 1,4-dioxane, tetrahydrofuran, ethylene glycol monomethyl ether,ethylene glycol dimethyl ether, diethylene glycol monomethyl ether,propylene glycol monomethyl ether, dipropylene glycol monomethyl ether,3-methoxy-3-methyl-1-butanol, etc.); aliphatic hydrocarbons (e.g.hexane, cyclohexane, kerosine, coal oil, burning oil, machine oil,etc.); aromatic hydrocarbons (e.g. toluene, xylene, ethylbenzene,dodecylbenzene, phenyl xylyl ethane, solvent naphtha, methylnaphthalene,etc.); halogenated hydrocarbons (e.g. dichloromethane, trichloroethane,chloroform, carbon tetrachloride, etc.); acid amides (e.g.N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,N-octylpyrrolidone, etc.); esters (e.g. butyl lactate, ethyl acetate,butyl acetate, isopropyl myristate, ethyl oleate, diisopropyl adipate,diisobutyl adipate, propylene glycol monomethyl ether acetate, fattyacid glycerin ester, γ-butyrolactone, etc.); nitriles (e.g.acetonitrile, isobutyronitrile, propionitrile, etc.); carbonates (e.g.propylene carbonate, etc.); and vegetable oils (e.g. soybean oil, oliveoil, linseed oil, coconut oil, copra oil, peanut oil, wheat germ oil,almond oil, sesame oil, mineral oil, rosemary oil, geranium oil,rapeseed oil, cottonseed oil, corn oil, safflower oil, orange oil,etc.). In the above-mentioned preparation, only a single type of liquidcarrier may be used, or two or more types of liquid carriers may also beused. Preferably, one or more types to three or less types of liquidcarriers are used. When two or more types of the liquid carriers areused, the liquid carriers may be mixed at an appropriate ratio and maybe then used, depending on intended use and the like.

Examples of the solid carrier (diluent/thickener) include: thesubstances listed in the EPA list (List Nos. 4A and 4B); andmicropowders and grains such as vegetable flours (e.g. soybean flour,tobacco flour, wheat flour, wood flour, etc.); mineral powders (e.g.clay such as kaoline clay, Fubasami clay, bentonite or Japanese acidclay; talc such as talcum powder or Roseki powder; silica such asdiatomaceous earth or mica powder; etc.); synthetic hydrated siliconoxide; alumina; talc; ceramic; other inorganic minerals (sericite,quartz, sulfur, activated carbon, calcium carbonate, hydrated silica,etc.); and chemical fertilizers (ammonium sulfate, ammonium phosphate,ammonium nitrate, urea, ammonium chloride). In the above-mentionedpreparation, only a single type of the solid carrier may be used, or twoor more types of the solid carriers may also be used. Preferably, one ormore types to three or less types of the solid carriers are used. Whentwo or more types of the solid carriers are used, the solid carriers maybe mixed at an appropriate ratio and may be then used, depending onintended use and the like.

Examples of the gaseous carrier include the substances disclosed in theEPA list (List Nos. 4A and 4B), fluorocarbon, butane gas, LPG (liquefiedpetroleum gas), dimethyl ether, and carbon dioxide. In theabove-mentioned preparation, only a single type of the gaseous carriermay be used, or two or more types of the gaseous carriers may also beused. Preferably, one or more types to three or less types of thegaseous carriers are used. When two or more types of the gaseouscarriers are used, the gaseous carriers may be mixed at an appropriateratio and may be then used, depending on intended use and the like. Itmay also be used in combination with the liquid carrier.

Examples of the ointment base include: the substances disclosed in theEPA list (List Nos. 4A and 4B); polyethylene glycol; pectin; polyhydricalcohol esters of higher fatty acids, such as glycerin monostearate;cellulose derivatives such as methylcellulose; sodium alginate; higheralcohol; polyhydric alcohol such as glycerin; Vaseline; whitepetrolatum; liquid paraffin; lard; various types of vegetable oils;lanolin; anhydrous lanolin; hydrogenated oil; and resins. In theabove-mentioned preparation, only a single type of ointment base may beused, or two or more types of the ointment bases may also be used.Preferably, one or more types to three or less types of the ointmentbases are used. When two or more types of the ointment bases are used,the ointment bases may be mixed at an appropriate ratio and may be thenused, depending on intended use and the like. Otherwise, the surfactantsas described below may be added to the medicament, and may be then used.

In the medicament, a surfactant may be used as an emulsifier, aspreading agent, a penetrant, a dispersant, or the like.

Examples of such surfactant include nonionic and anionic surfactantssuch as soaps; polyoxyethylene alkyl aryl ethers [e.g. Noigen (productname), EA142 (product name), manufactured by Dai-Ich Kogyo Seiyaku Co.,Ltd; Nonal (product name), manufactured by Toho Chemical Industry Co.,Ltd.]; alkyl sulfates [e.g. Emal 10 (product name), Emal 40 (productname), manufactured by Kao Corporation]; alkylbenzene sulfonates [e.g.Neogen (product name), Neogen T (product name), manufactured by Dai-IchiKogyo Seiyaku Co., Ltd.; Neoperex, manufactured by Kao Corporation];polyethylene glycol ethers [e.g. Nonipol 85 (product name), Nonipol 100(product name), Nonipol 160 (product name), manufactured by SanyoChemical Industries Ltd.]; polyoxyethylene alkyl ethers [e.g. NoigenET-135 (product name), manufactured by Dai-Ich Kogyo Seiyaku Co., Ltd.];polyoxyethylene-polyoxypropylene block polymers [e.g. Newpol PE-64(product name), Sanyo Chemical Industries Ltd.]; polyhydric alcoholesters [e.g. Tween 20 (product name), Tween 80 (product name),manufactured by Kao Corporation]; alkyl sulfosuccinates [e.g. SanmorinOT20 (product name), Sanyo Chemical Industries Ltd.; Newkalgen EX70(product name), Takemoto Yushi K.K.]; alkyl naphthalene sulfonates [e.g.Newkalgen WG-1 (product name), Takemoto Yushi K.K.]; and alkenylsulfonates [e.g. Sorpol 5115 (product name), Toho Chemical Co., Ltd.].One or more types of (preferably one or more types to three or lesstypes of) such surfactants may be mixed at an appropriate ratio and maybe then used.

Other specific examples of the auxiliary agent for the medicamentinclude casein, gelatin, sugars (starch, gum Arabic, a cellulosederivative, alginic acid, etc.), a lignin derivative, bentonite, asynthetic water-soluble polymer (polyvinyl alcohol,polyvinylpyrrolidone, polyacrylic acids, etc.), PAP (acidic isopropylphosphate), BHT (2,6-di-tert-butyl-4-methylphenol), and BHA (a mixtureof 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol).

The composition of the present invention may also comprise aninsecticide, an acaricide, a nematicide, a microbicide, a plant hormoneagent, a plant growth-control agent, a herbicide, a synergist or anantidote, in addition to the present active compound.

The content of the present active compound in the composition of thepresent invention is generally 0.01% to 95% by weight, preferablyapproximately 0.1% to 90% by weight, and more preferably approximately5% to 70% by weight, based on the total amount of the composition of thepresent invention.

Specifically, when the composition of the present invention is in theform of an emulsion, a liquid agent, a wettable powder, or a granulewettable powder, the content of the present active compound is generallyapproximately 1% to 90% by weight, and preferably approximately 5% to50% by weight, based on the total amount of the composition of thepresent invention. When the composition of the present invention is inthe form of an oil agent or a powder agent, the content of the presentactive compound is generally approximately 0.1% to 50% by weight, andpreferably approximately 0.1% to 20% by weight, based on the totalamount of the composition of the present invention. When the compositionof the present invention is in the form of a granule agent, the contentof the present active compound is generally approximately 0.1% to 50% byweight, and preferably approximately 0.5% to 20% by weight, based on thetotal amount of the composition of the present invention.

The content of the other agricultural active ingredient (e.g. aninsecticide, a herbicide, an acaricide and/or a microbicide) mixed intothe composition of the present invention is preferably approximately 1%to 80% by weight, and more preferably approximately 1% to 20%, based onthe total amount of the composition of the present invention.

The content of an additive other than the active ingredient differsdepending on the type or content of an agricultural active ingredient,the formulation of a medicament, and the like. It is generallyapproximately 0.001% to 99.9% by weight, and preferably approximately 1%to 99% by weight, based on the total amount of the composition of thepresent invention. For example, a surfactant may be added at apercentage of generally approximately 1% to 20% by weight, andpreferably approximately 1% to 15% by weight; a flowable agent may beadded at a percentage of approximately 1% to 20% by weight; and acarrier may be added at a percentage of approximately 1% to 90% byweight, and preferably approximately 1% to 70% by weight, based on thetotal amount of the composition of the present invention. When thecomposition of the present invention is in the form of a liquid agent, asurfactant may be added at a percentage of generally 1% to 20% byweight, and preferably approximately 1% to 10% by weight, and water maybe added at a percentage of approximately 20% to 90% by weight, based onthe total amount of the composition of the present invention. Moreover,an emulsion, a wettable powder, a granule wettable powder, or the likemay be appropriately extended with water or the like (for example,approximately 100 to 5,000 times) before use, and it may be thendiffused.

Typical examples of the insecticide, acaricide, nematicide, microbicide,plant hormone agent, plant growth-control agent, herbicide, synergist,and antidote will be given below.

Examples of the insecticides include the following compounds:

(1) Organophosphorus compounds

acephate, Aluminium phosphide, butathiofos, cadusafos, chlorethoxyfos,chlorfenvinphos, chlorpyrifos, chlorpyrifos-methyl, cyanophos: CYAP,diazinon, dichlorodiisopropyl ether, dichlofenthion: ECP, dichlorvos:DDVP, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos,etrimfos, fenthion: MPP, fenitrothion: MEP, fosthiazate, formothion,Hydrogen phosphide, isofenphos, isoxathion, malathion, mesulfenfos,methidathion: DMTP, monocrotophos, naled: BRP, oxydeprofos: ESP,parathion, phosalone, phosmet: PMP, pirimiphos-methyl, pyridafenthion,quinalphos, phenthoate: PAP, profenofos, propaphos, prothiofos,pyraclorfos, salithion, sulprofos, tebupirimfos, temephos,tetrachlorvinphos, terbufos, thiometon, trichlorphon: DEP, vamidothion,phorate, cadusafos and the like;

(2) Carbamate compounds

alanycarb, bendiocarb, benfuracarb, BPMC, carbaryl, carbofuran,carbosulfan, cloethocarb, ethiofencarb, fenobucarb, fenothiocarb,fenoxycarb, furathiocarb, isoprocarb: MIPC, metolcarb, methomyl,methiocarb, NAC, oxamyl, pirimicarb, propoxur: PHC, XMC, thiodicarb,xylylcarb, aldicarb and the like;

(3) Synthetic pyrethroid compounds

acrinathrin, allethrin, benfluthrin, beta-cyfluthrin, bifenthrin,cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin,esfenvalerate, ethofenprox, fenpropathrin, fenvalerate, flucythrinate,flufenoprox, flumethrin, fluvalinate, halfenprox, imiprothrin,permethrin, prallethrin, pyrethrins, resmethrin, sigma-cypermethrin,silafluofen, tefluthrin, tralomethrin, transfluthrin, tetramethrin,phenothrin, cyphenothrin, alpha-cypermethrin, zeta-cypermethrin,lambda-cyhalothrin, gamma-cyhalothrin, furamethrin, tau-fluvalinate,metofluthrin, profluthrin, dimefluthrin,2,3,5,6-tetrafluoro-4-(methoxymethyl)benzil(EZ)-(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-prop-1-enylcyclopropanecarboxylate,2,3,5,6-tetrafluoro-4-methylbenzyl(EZ)-(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-prop-1-enylcyclopropanecarboxylate,2,3,5,6-tetrafluoro-4-(methoxymethyl)benzil(1RS,3RS;1RS,3SR)-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylateand the like;

(4) Nereistoxin compounds

cartap, bensultap, thiocyclam, monosultap, bisultap and the like;

(5) Neonicotinoid compounds

imidacloprid, nitenpyram, acetamiprid, thiamethoxam, thiacloprid,dinotefuran, clothianidin and the like;

(6) Benzoylurea compounds

chlorfluazuron, bistrifluoron, diafenthiuron, diflubenzuron, fluazuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron,noviflumuron, teflubenzuron, triflumuron, triazuron and the like;

(7) Phenylpyrazole compounds

acetoprole, ethiprole, fipronil, vaniliprole, pyriprole, pyrafluproleand the like;

(8) Bt toxin insecticides

Fresh spores derived from Bacillus thuringiensis, crystalline toxinsgenerated therefrom, and the mixtures thereof;

(9) Hydrazine compounds

chromafenozide, halofenozide, methoxyfenozide, tebufenozide and thelike;

(10) Organnochlorine compounds

aldrin, dieldrin, dienochlor, endosulfan, methoxychlor and the like;

(11) Natural insecticides

machine oil, nicotine-sulfate;

(12) Other types of insecticides

avermectin-B, bromopropylate, buprofezin, chlorphenapyr, cyromazine,D-D(1,3-Dichloropropene), emamectin-benzoate, fenazaquin, flupyrazofos,hydroprene, methoprene, indoxacarb, metoxadiazone, milbemycin-A,pymetrozine, pyridalyl, pyriproxyfen, spinosad, sulfluramid,tolfenpyrad, triazamate, flubendiamide, lepimectin, Arsenic acid,benclothiaz, Calcium cyanamide, Calcium polysulfide, chlordane, DDT,DSP, flufenerim, flonicamid, flurimfen, formetanate, metam-ammonium,metam-sodium, Methyl bromide, Potassium oleate, protrifenbute,spiromesifen, Sulfur, metaflumizone, spirotetramat, pyrifluquinazone,spinetoram, chlorantraniliprole, tralopyril, and a compound representedby the following formula (A):

wherein R1 represents Me, Cl, Br, or F,

R2 represents F, Cl, Br, C1-C4 haloalkyl, or C1-C4 haloalkoxy,

R3 represents F, Cl, or Br,

R4 represents H, one or more halogen atoms, C1-C4 alkyl optionallysubstituted with CN, SMe, S(O)Me, S(0)₂Me and OMe, C3-C4 alkenyl, C3-C4alkynyl, or C3-C5 cycloalkylalkyl,

R5 represents H or Me,

R6 represents H, F, or Cl, and

F7 represents H, F, or Cl.

Examples of the acaricides (acarcidal active ingredients) include

acequinocyl, amitraz, benzoximate, bifenaate, bromopropylate,chinomethionat, chlorobenzilate, CPCBS(chlorfenson), clofentezine,cyflumetofen, kelthane (dicofol), etoxazole, fenbutatin oxide,fenothiocarb, fenpyroximate, fluacrypyrim, fluproxyfen, hexythiazox,propargite: BPPS, polynactins, pyridaben, Pyrimidifen, tebufenpyrad,tetradifon, spirodiclofen, spiromesifen, spirotetramat, amidoflumet,cyenopyrafen and the like, and

examples of the nematicides (nematicidal active ingredients) includeDCIP, fosthiazate, levamisol hydrochloride, methylisothiocyanate;morantel tartarate, and imicyafos.

Examples of the fungicides include:

azole-based fungicidal compounds such as propiconazole, prothioconazole,triadimenol, prochloraz, penconazole, tebuconazole, flusilazole,diniconazole, bromuconazole, epoxiconazole, difenoconazole,cyproconazole, metconazole, triflumizole, tetraconazole, myclobutanil,fenbuconazole, hexaconazole, fluquinconazole, triticonazole, bitertanol,imazalil, and flutriafol;

cyclic amine-based fungicidal compounds such as fenpropimorph,tridemorph, and fenpropidin;

benzimidazole-based fungicidal compounds such as carbendezim, benomyl,thiabendazole, and thiophanate-methyl;

procymidone; cyprodinil; pyrimethanil; diethofencarb; thiuram;fluazinam; mancozeb; iprodione; vinclozolin; chlorothalonil; captan;mepanipyrim; fenpiclonil; fludioxonil; dichlofluanid; folpet;kresoxim-methyl; azoxystrobin; trifloxystrobin; fluoxastrobin;picoxystrobin; pyraclostrobin; dimoxystrobin; pyribencarb; spiroxamine;quinoxyfen; fenhexamid; famoxadone; fenamidone; zoxamide; ethaboxam;amisuibrom; iprovalicarb; benthiavalicarb; cyazofamid; mandipropamid;boscalid; penthiopyrad; metrafenone; fluopiran; bixafen; cyflufenamid,and proquinazid.

Examples of the herbicides include:

(1) Phenoxy fatty acid-based herbicidal compounds

such as 2,4-PA, MCP, MCPB, phenothiol, mecoprop, fluoroxypyr, triclopyr,clomeprop, and naproanilide;

(2) Benzoic acid-based herbicidal compounds

such as 2,3,6-TBA, dicamba, clopyralid, picloram, aminopyralid,quinclorac, and quinmerac;

(3) Urea-based herbicidal compounds

such as diuron, linuron, chlortoluron, isoproturon, fluometuron,isouron, tebuthiuron, methabenzthiazuron, cumyluron, daimuron, andmethyl-daimuron;

(4) Triazine-based herbicidal compounds

such as atrazine, ametoryn, cyanazine, simazine, propazine, simetryn,dimethametryn, prometryn, metribuzin, and triaziflam;

(5) Bipyridinium-based herbicidal compounds

such as paraquat and diquat;

(6) Hydroxybenzonitrile-based herbicidal compounds

such as bromoxynil and ioxynil;

(7) Dinitroaniline-based herbicidal compounds

such as pendimethalin, prodiamine, and trifluralin;

(8) Organic phosphorus-based herbicidal compounds

such as amiprofos-methyl, butamifos, bensulide, piperophos, anilofos,glyphosate, glufosinate, and bialaphos;

(9) Carbamate-based herbicidal compounds

such as di-allate, tri-allate, EPTC, butylate, benthiocarb, esprocarb,molinate, dimepiperate, swep, chlorpropham, phenmedipham, phenisopham,pyributicarb, and asulam;

(10) Acid amide-based herbicidal compounds

such as propanil, propyzamide, bromobutide, and etobenzanid;

(11) Chloroacetanilide-based herbicidal compounds

such as acetochlor, alachlor, butachlor, dimethenamid, propachlor,metazachior, metolachlor, pretilachlor, thenylchlor, and pethoxamid;

(12) Diphenyl ether-based herbicidal compounds

such as acifluorfen-sodium, bifenox, oxyfluorfen, lactofen, fomesafen,chlomethoxynil, and aclonifen;

(13) Cyclic imide-based herbicidal compounds

such as oxadiazon, cinidon-ethyl, carfentrazone-ethyl, surfentrazone,flumiclorac-pentyl, flumioxazin, pyraflufen-ethyl, oxadiargyl,pentoxazone, fluthiacet-methyl, butafenacil, and benzfendizone;

(14) Pyrazole-based herbicidal compounds

such as benzofenap, pyrazolate, pyrazoxyfen, topramezone, andpyrasulfotole;

(15) Triketone-based herbicidal compounds

such as isoxaflutole, benzobicyclon, sulcotrione, mesotrione,tembotrione, and tefuryltrione;

(16) Aryloxyphenoxypropionic acid-based herbicidal compounds

such as clodinafop-propargyl, cyhalofop-butyl, diclofop-methyl,fenoxaprop-ethyl, fluazifop-butyl, haloxyfop-methyl, quizalofop-ethyl,and metamifop;

(17) Trione oxime-based herbicidal compounds

such as alloxydim-sodium, sethoxydim, butroxydim, clethodim,cloproxydim, cycloxydim, tepraloxydim, tralkoxydim, and profoxydim;

(18) Sulfonylurea-based herbicidal compounds

such as chlorsulfuron, sulfometuron-methyl, metsulfuron-methyl,chlorimuron-ethyl, tribenuron-methyl, triasulfuron, bensulfuron-methyl,thifensulfuron-methyl, pyrazosulfuron-ethyl, primisulfuron-methyl,nicosulfuron, amidosulfuron, cinosulfuron, imazosulfuron, rimsulfuron,halosulfuron-methyl, prosulfuron, ethametsulfuron-methyl,triflusulfuron-methyl, flazasulfuron, cyclosulfamuron, flupyrsulfuron,sulfosulfuron, azimsulfuron, ethoxysulfuron, oxasulfuron,iodosulfuron-methyl-sodium, foramsulfuron, mesosulfuron-methyl,trifloxysulfuron, tritosulfuron, orthosulfamuron, flucetosulfuron, and1-(2-chloro-6-propylimidazo[1,2-a]pyridazin-3-ylsulfonyl)-3-(4,6-dimethoxypyrimidin-2-yl)urea;

(19) Imidazolinone-based herbicidal compounds

such as imazamethabenz-methyl, imazamethapyr, imazamox, imazapyr,imazaquin, and imazethapyr;

(20) Sulfonamide-based herbicidal compounds

such as flumetsulam, metosulam, diclosulam, florasulam,cloransulam-methyl, penoxsulam, and pyroxsulam;

(21) Pyrimidinyloxybenzoic acid-based herbicidal compounds

such as pyrithiobac-sodium, bispyribac-sodium, pyriminobac-methyl,pyribenzoxim, pyriftalid, and pyrimisulfan;

(22) Other herbicidal compounds

such as bentazon, bromacil, terbacil, chlorthiamid, isoxaben, dinoseb,amitrole, cinmethylin, tridiphane, dalapon, diflufenzopyr-sodium,dithiopyr, thiazopyr, flucarbazone-sodium, propoxycarbazone-sodium,mefenacet, flufenacet, fentrazamide, cafenstrole, indanofan,oxaziclomefone, benfuresate, ACN, pyridate, chloridazon, norflurazon,flurtamone, diflufenican, picolinafen, beflubutamid, clomazone,amicarbazone, pinoxaden, pyraclonil, pyroxasulfone, andthiencarbazone-methyl.

Examples of the plant growth regulators include:

hymexazol, paclobutrazol, uniconazole-P, inabenfide,prohexadione-calcium, aviglycine, 1-naphthylacetamide, abscisic acid,indolebutyric acid, ethychlozate ethyl, ethephon, cloxyfonac,chlormequat, dichlorprop, gibberellin, prohydrojasmon,benzylaminopurine, forchlorfenuron, maleic hydrazide, calcium peroxide,mepiquat-chloride, and 4-CPA (4-chlorophenoxyacetic acid).

Examples of the synergists include:

piperonyl butoxide, sesamex, sulfoxide,N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide (MGK 264),N-declyimidazole, WARF-antiresistant, TBPT, TPP, IBP, PSCP, methyliodide (CH₃I), t-phenylbutenone, diethylmaleate, DMC, FDMC, ETP, andETN.

Examples of the safeners include:

benoxacor, cloquintocet-mexyl, cyometrinil, daimuron, dichlormid,fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole,mefenpyr-diethyl, MG191, oxabetrinil, allidochlor, isoxadifen-ethyl,cyprosulfamide, fluxofenim, and 1,8-naphthalic anhydride.

The composition of the present invention or the present active compoundcan be used simultaneously with agents for controlling harmful organismssuch as natural enemy organisms or natural enemy microorganisms.

Typical examples of such natural enemy organisms, natural enemymicroorganisms, etc., will be given below.

staphylinidae, Braconidae, Ichneumonidae, Pseudanastatus,Tenthredimidae, Siricidae, Orussidae, Aphididae, Eulophidae,Franklinothrips, Lycosidae, Aphelinidae, Tessaratominae, Cecidomyiidae,Syrphidae, Anthocoridae, Phytoseiidae, Chrysopidae, Mantidae,Coccinelidae, Libellulidae, Harpalidae, Formicidae, Beauveria,Verticillium, Paecilomyces, muscardine fungi, nucleopolyhedrovirus,granulosis virus, Cytoplasmic polyhedrosis virus, entomophilicnematodes, and nematocidal fungi such as Pasteuria sp. andMonacrosporium sp.

An arthropod pest control method, which comprises applying an effectiveamount of the present active compound to arthropod pests or areas wherearthropod pests live is also one embodiment of the present invention.

Examples of arthropod pests, on which the present active compound has aneffect, include harmful insects and harmful acarids. Specific examplesare given below:

Insect pests belonging to Hemiptera, including: Delphacidae such asLaodelphax striatellus, Nilaparvata lugens, or Sogatella furcifera;leafhoppers such as Nephotettix cincticeps, Nephotettix virescens, orEmpoasca onukii; aphids such as Aphis gossypii, Myzus persicae,Brevicoryne brassicae, Aphis spiraecola, Macrosiphum euphorbiae,Aulacorthum solani, Rhopalosiphum padi, Toxoptera citricidus, orHyalopterus pruni; Pentatomorpha such as Nezara antennata, Riptortusclavetus, Leptocorisa chinensis, Eysarcoris parvus, or Halyomorphamista; white flies such as Trialeurodes vaporariorum, Bemisia tabaci,Dialeurodes citri, or Aleurocanthus spiniferus; scale insects such asAonidiella aurantii, Comstockaspis perniciosa, Unaspis citri,Ceroplastes rubens, Icerya purchasi, Planococcus kraunhiae, Pseudococcuslongispinis, or Pseudaulacaspis pentagona; tingis flies; bedbugs such asCimex lectularius; psyllas; and others;

Insect pests belonging to Lepidoptera, including: pyralids such as Chilosuppressalis, Tryporyza incertulas, Cnaphalocrocis medinalis, Notarchaderogata, Plodia interpunctella, Ostrinia furnacalis, Hellula undalis,or Pediasia teterrellus; owlet moths such as Spodoptera litura,Spodoptera exigua, Pseudaletia separata, Mamestra brassicae, Agrotisipsilon, Plusia nigrisigna, genus Trichoplusia, genus Heliothis, orgenus Helicoverpa; cabbage butterflies such as Pieris rapae; tortrixessuch as genus Adoxopheys, Grapholita molesta, Leguminivoraglycinivorella, Matsumuraeses azukivora, Adoxophyes orana fasciata,Adoxophyes honmai, Homona magnanima, Archips fuscocupreanus, or Cydiapomonella; Gracillariidae such as Caloptilia theivora or Phyllonorycterringoneella; Carposinidae such as Carposina niponensis; Lyonetiidae suchas genus Lyonetia; Liparidae such as genus Lymantria or genus Euproctis;Yponomeutidae such as Plutella xylostella; Gelechiidae such asPectinophora gossypiella or Phthorimaea operculella; Arctiidae such asHyphantria cunea; Tineidae such as Tinea translucens or Tineolabisselliella; and others;

Insect pests belonging to Thysanoptera, including: thysanopterans suchas Frankliniella occidentalis, Thrips parmi, Scirtothrips dorsalis,Thrips tabaci, or Frankliniella intonsa; and others;

Insect pests belonging to Diptera, including: Culex such as Culexpipiens pallens, Culex tritaeniorhynchus, or Culex quinquefasciatus;genus Aedes such as Aedes aegypti or Aedes albopictus; genus Anophelessuch as Anopheles sinensis; Chironomus; Muscidae such as Musca domesticaor Muscina stabulans; Calliphoridae; Sarcophagidae; Fanniidae;Anthomyiidae such as Delia platura or Delia antiqua; Agromyzidae such asAgromyza oryzae, Hydrellia griseola, Liriomyza sativae, Liriomyzatrifolii, or Chromatomyia horticola; Carnoidea such as Chlorops oryzae;Tephritoidea such as Dacus cucurbitae or Ceratitis capitata; Drosophila;Phoridae such as Megaselia spiracularis; Psychodidae such as Clogmiaalbipunctata; Simuliidae; Tabanidae such as Tabanus trigonus; Stomoxys;and others;

Insect pests belonging to Coleoptera, including: Corn Rootworms such asDiabrotica virgifera virgifera or Diabrotica undecimpunctata howardi;Scarabaeidae such as Anomala cuprea, Anomala rufocuprea, or Popilliajaponica; Curculionidae such as Sitophilus zeamais, Lissorhoptrusoryzophilus, Callosobruchuys chienensis, Echinocnemus squameus,Anthonomus grandis, or Sphenophorus venatus; Tenebrionoidea such asTenebrio molitor or Tribolium castaneum;

Chrysomelidae such as Oulema oryzae, Aulacophora femoralis, Phyllotretastriolata, or Leptinotarsa decemlineata; Dermestidae such as Anthrenusverbasci or Dermestes maculates; Anobiidae such as Lasiodermaserricorne; Epilachna such as Epilachna vigintioctopunctata; Scolytidaesuch as Lyctus brunneus or Tomicus piniperda; Bostrichidae; Ptimidae;Cerambycidae such as Anoplophora malasiaca; Agriotes spp.; Paederusfuscipes, and others;

Insect pests belonging to Orthoptera, including: Locusta migratoria,Gryllotalpa Africana, Oxya yezoensis, Oxya japonica, Grylloidea; andothers;

Insect pests belonging to Siphonaptera, including Ctenocephalides felis,Ctenocephalides canis, Pulex irritans, Xenopsylla cheopis, and others;

Insect pests belonging to Anoplura, including Pediculus humanuscorporis, Phthirus pubis, Haematopinus eurysternus, Dalmalinia ovis,Haematopinus suis, and others;

Insect pests belonging to Hymenoptera, including: Formicidae such asMonomorium pharaosis, Formica furca japonica, Ochetellus glaber,Pristomyrmex pungens, Pheidole noda, Acromyrmex spp., Solenopsis spp.;Vespidae; Bethylidae; Tenthredimidae such as Athalia rosae or Athaliajaponica; and others;

Insect pests belonging to Blattariae, including: Blattella germanica,Periplaneta fuliginosa, Periplaneta americana, Periplaneta brunnea,Blatta orientalis, and others;

Insect pests belonging to Acarina, including: Tetranychidae such asTetranychus urticae, Tetranychus kanzawai, Panonychus citri, Panonychusulmi, or genus Oligonicus; Eriophyidae such as Aculops pelekassi,Phyllocoptruta citri, Aculops lycopersici, Calacarus carinatus,Acaphylla theavagrans, Eriophyes chibaensis, or Aculus schlechtendali;Tarsonemidae such as Polyphagotarsonemus latus; Tenuipalpidae such asBrevipalpus phoenicis; Tuckerellidae; Ixodidae such as Haemaphysalislongicornis, Haemaphysalis flava, Dermacentor taiwanicus, Ixodes ovatus,Ixodes persulcatus, Ixodes scapularis, Boophilus microplus, orRhipicephalus sanguineus; Acaridae such as Tyrophagus putrescentiae orTyrophagus similis; Epidermoptidae such as Dermatophagoides farinae orDermatophagoides ptrenyssnus; Cheyletidae such as Cheyletus eruditus,Cheyletus malaccensis, or Cheyletus moorei; Dermanyssidae such asOrnithonyssus bacoti, Ornithonyssus sylvairum, or Dermanyssus gallinae;Trombiculidae such as Leptotrombidium akamushi; Arachnida such asChiracanthium japonicum or Latrodectus hasseltii; and others;

Chilopoda including Thereuonema hilgendorfi, Scolopendra subspinipes,and others;

Diplopoda including Oxidus gracilis, Nedyopus tambanus, and others;

Isopoda including Armadillidium vulgare, and others; and

Gastropoda including Limax marginatus, Limax flavus, and others.

In the controlling method of the present invention, arthropod pests, onwhich the present active compound has a high effect, are insect pestsbelonging to Hemiptera.

Among the arthropod pests, an example of insect pest to timber productsis Isoptera. Specific examples of such Isoptera will be given below.

Mastotermitidae, Termopsidae [genus Zootermopsis, genus Archotermopsis,genus Hodotermopsis, genus Porotermes, and genus Stolotermes],Kalotermitidae [genus Kalotermes, genus Neotermes, genus Cryptotermes,genus Incistermes, and genus Glyptotermes], Hodotermitidae [genusHodotermes, genus Microhodotermes, and genus Anacanthotermes],Rhinotermitidae [genus Reticulitermes, genus Heterotermes, genusCoptotermes, and genus Schedolinotermes], Serritermitidae, andTermitidae {genus Amitermes, genus Drepanotermes, genus Hopitalitermes,genus Trinervitermes, genus Macrotermes, genus Odontotermes, genusMicrotermes, genus Nasutitermes, genus Pericapritermes, and genusAnoplotermes}.

Of these, specific examples of Isoptera as a target to be controlledinclude Reticulitermes speratus, Coptotermes formosanus, Incisitermesminor, Cryptotermes domesticus, Odontotermes formosanus, Neotermeskoshunensis, Glyptotermes satsumensis, Glyptotermes nakajimai,Glyptotermes fuscus, Glyptotermes kodamai, Glyptotermes kushimensis,Hodotermopsis japonica, Coptotermes guangzhoensis, Reticulitermesmiyatakei, Reticulitermes flaviceps amamianus, Reticulitermes sp.,Nasutitermes takasagoensis, Pericapritermes nitobei, Sinocapritermesmushae, Reticulitermes flavipes, Reticulitermes hesperus, Reticulitermesvirginicus, Reticulitermes tibialis, Heterotermes aureus, andZootermopsis nevadensis.

Insects other than Isoptera that are harmful to timber products includecoleopteran insects such as Lyctidae, Bostrichidae, Anobiidae, andCerambycidae.

The present active compound can be used to control arthropods internallyor externally parasitizing in vertebrate animals such as a human, abovine, a sheep, a goat, a swine, a fowl, a dog, a cat, and fish in thefield of treatment of animal diseases and in the livestock industry, soas to maintain public health. Examples of such harmful organismsinclude: Ixodes spp. such as Ixodes scapularis; Boophilus spp. such asBoophilus microplus; Amblyomma spp.; Hyalomma spp.; Rhipicephalus spp.such as Rhipicephalus sanguineus; Haemaphysalis spp. such asHaemaphysalis longicornis; Dermacentor spp.; Ornithodoros spp. such asOrnithodoros moubata; Dermahyssus gallinae; Ornithonyssus sylviarum;Sarcoptes spp. such as Sarcoptes scabiei; Psoroptes spp.; Chorioptesspp.; Demodex spp.; Eutrombicula spp.; Aedes spp. such as Aedesalbopictus; Anopheles spp.; Culex spp.; Culicodes spp.; Musca spp.;Hypoderma spp.; Gasterophilus spp.; Haematobia spp.; Tabanus spp.;Simulium spp.; Triatoma spp.; Phthiraptera such as Damalinia spp.,Linognathus spp., or Haematopinus spp.; Ctenocephalides spp. such asCtenocephalides felis; Xenosylla spp.; and Monomorium pharaonis.

According to the control method of the present invention, the presentactive compound may be directly applied without any other ingredients,or the present active compound may be applied in combination with theabove-described other agents such as an insecticide, an acaricide, anematicide, or a microbicide. Alternatively, the present active compoundmay also be applied in combination with natural enemy organisms ornatural enemy microorganisms. Further, the composition of the presentinvention may be used as the present active compound.

Examples of the areas where the arthropod pests live include a paddyfield, a dry field, a farm land, a tea garden, an orchard, anonagricultural land, a house, a seedling-raising tray, aseedling-raising box, a seedling-raising soil, a seedling-raising mat,and a water culture medium in a hydroponic farm.

In the control method, the present active compound can be applied toarthropod pests or areas where arthropod pests live by allowing thecompound to come into contact with the arthropod pests or causing thearthropod pests to ingest the compound, according to the same method asin the case of conventional arthropod pest control agents.

Examples of such application method include a spraying treatment, a soiltreatment, a seed treatment, and a water culture medium treatment.

The spraying treatment is a treatment method, which comprises sprayingan active ingredient (the present active compound) onto the surface of aplant body, for example, according to foliage spraying or truckspraying, or onto an arthropod pest itself, so as to exhibit acontrolling effect on the arthropod pests.

The soil treatment is, for example, a treatment method, which comprisesgiving an active ingredient to the root portion of a crop to beprotected so as to directly control arthropod pests, or penetrating suchactive ingredient into a plant body to control such arthropod pests.

Specific examples of the soil treatment include a planting holetreatment (planting hole spraying and planting hole-treated soilmixture), a seedling treatment (seedling spraying, seedling soilmixture, seedling irrigation, and a seedling treatment in the latterpart of a seedling-raising period), a planting ditch treatment (plantingditch spraying and planting ditch soil mixture), a planting rowtreatment (planting row spraying, planting row soil mixture, andplanting row spraying in a growing period), a planting row treatmentduring a seeding time (planting row spraying during a seeding time andplanting row soil mixture during a seeding time), a total treatment(total soil spraying and total soil mixture), a side row treatment, awater surface treatment (water surface application and water surfaceapplication after flooding), other soil spraying treatments (thespraying of a granule agent onto leave during a growing period, thespraying of the agent to below the tree crown or around the main stem,the spraying of the agent onto the soil surface, soil surface mixture,planting hole spraying, furrow surface spraying, and the spraying of theagent to between stocks), other irrigation treatments (soil irrigation,irrigation in a seeding-raising period, an agent injection treatment,irrigation to a soil-contacting portion of plant, agent drip irrigation,and chemigation), a seedling-raising box treatment (seedling-raising boxspraying, seedling-raising box irrigation, and the flooding of aseedling-raising box with an agent liquid), a seedling-raising traytreatment (seedling-raising tray spraying, seedling-raising trayirrigation, and the flooding of a seedling-raising tray with an agentliquid), a seedbed treatment (seedbed spraying, seedbed irrigation,flooded nursery seedbed spraying, and nursery immersion), a seedbed soilmixing treatment (seedbed soil mixing, seedbed soil mixture beforeseeding, spraying before cover soil in a seeding time, spraying aftercover soil in a seeding time, and cover soil mixing), and othertreatments (seeding soil mixture, plowing, surface soil mixture, themixing of a rain-dropping portion of soil, a planting positiontreatment, the spraying of a granule agent to inflorescence, and pastefertilizer mixture).

The seed treatment is a treatment method, which comprises directlytreating with an active ingredient, seeds, seed potatoes, bulbs, etc. ofcrops to be protected, or treating the neighborhood thereof with suchactive ingredient, so as to exhibit a control effect on arthropod pests.Specific examples of the seed treatment include a spraying treatment, asmearing treatment, an immersion treatment, an impregnation treatment,an application treatment, a film coating treatment, and a pellet coatingtreatment.

The water culture medium treatment is, for example, a treatment method,which comprises treating a water culture medium or the like with anactive ingredient in order to infiltrate the active ingredient from theroot portion of a crop to be protected to the internal portion thereof,so as to protect the crop from the damage caused by arthropod pests.Specific examples of the water culture medium treatment include waterculture medium mixture and water culture medium incorporation.

The present active compound can be used as an arthropod pest controlagent in agricultural or nonagricultural lands such as a farm land, apaddy field, a lawn, and an orchard.

When the present active compound is used to control arthropod pests inthe agricultural field, the amount of application can be broadly altereddepending on an application period, an application site, an applicationmethod, etc. It is generally 1 to 10,000 g per 10,000 m². When thepresent active compound is formulated to be an emulsion, a wettablepowder, a flowable agent, etc., the active compound is diluted withwater to a concentration of 0.01 to 10,000 ppm. A powder agent, agranule agent, or the like is generally applied as it is.

The present active compound or a water dilution thereof may be directlysprayed to arthropod pests or plants, or it may also be subjected to thesoil treatment.

Otherwise, the present active compound may also applied using a resinpreparation that is processed in the form of a sheet or a cord. Theresin preparation comprising the present active compound may be twistedaround crops, strung around the neighborhood of the crops, or spread onthe planting soil.

In some cases, the present active compound may control insect pests inan agricultural land and the like, where the “crops” as described belowand the like are cultivated, without giving harmful effects on the cropsand the like.

Crops: corn, rice, wheat, barley, rye, oat, sorghum, cotton, soybean,peanut, buckwheat, sugarbeet, rapeseed, sunflower, sugarcane, tobacco,etc.

Vegetables: solanaceous vegetables (eggplant, tomato, pimento, pepper,potato, etc.), cucurbitaceous vegetables (cucumber, pumpkin, zucchini,watermelon, melon, etc.), brassicaceous vegetables (Japanese radish,turnip, horseradish, kohlrabi, Chinese cabbage, cabbage, leaf mustard,broccoli, cauliflower, etc.), asteraceous vegetables (burdock,Chrysanthemum coronarium, artichoke, lettuce, etc.), liliaceousvegetables (spring onion, onion, garlic, asparagus), umbelliferousvegetables (carrot, parsley, celery, parsnip, etc.), chenopodiaceousvegetables (spinach, silver beet, etc.), lamiaceous vegetables (Japanesebasil, mint, basil, etc.), strawberry, sweet potato, Dioscorea japonica,colocasia antiquorum, and others.

Fruit trees; pome fleshy fruits (apple, pear, Japanese pear, amboyna,quince, etc.), stone fleshy fruits (peach, plum, nectarine, Prunus mume,Prunus avium, apricot, prune, etc.), citrus fruits (Citrus unshiu,orange, lemon, lime, grapefruit, etc.), nuts (malon, walnuts, hazelnuts,almond, pistachio, cashew nuts, macadamia nuts, etc.), sap fruits(blueberry, cranberry, blackberry, raspberry, etc.), grape, Japanesepersimmon, olive, Eriobotrya japonica, banana, coffee, Phoenixdactylifera, Cocos nucifera, Elaeis guineensis, and others.

Trees other than fruit trees; tea tree, Morus alba, flowering plants,street trees (ash, birch, Benthamidia florida, Eucalyptus, Ginkgobiloba, lilac, maple, oak, poplar, Chinese redbud, Formosa sweet gum,plane tree, zelkova, Japanese arborvitae, fir, Japanese hemlock, needlejuniper, pine, Japanese spruce, and Japanese yew), Jatropha, and others.

Lawns: lawn grasses (Zoysia japonica, Zoysia tenuifolia, etc.), Bermudagrasses (Cynodon dactylon, etc.), bent grasses (redtop grass, Agrostisstolonifera L., Agrostis capillaris L., etc.), blue grasses (Kentuckybluegrass, Poatrivialis L., etc.), festuca (Festuca arundinacea Schreb.,Festuca rubra, creeping red fescue, etc.), ryegrasses (Australianryegrass, perennial ryegrass, etc.), rchard grass, timothy, and others.

Others; flowers, foliage plants, and others.

The “crops” include plants which have acquired resistance to herbicidesincluding HPPD inhibitors such as isoxaflutole, ALS inhibitors such asimazethapyr and thifensulfuron methyl, EPSP synthetase inhibitors,glutamine synthetase inhibitors, acetyl-CoA carboxylase inhibitors,bromoxynil, and the like, according to classical breeding methods orgene recombination technology.

Examples of the “crops” which have acquired resistance according toclassical breeding methods include: Clearfield [registered trademark]canola that is resistant to imidazolinone herbicides such asimazethapyr; and STS soybean that is resistant to sulfonylurea ALSinhibition-type herbicides such as thifensulfuron methyl.

Likewise, an example of the crops which have acquired resistance toacetyl-CoA carboxylase inhibitors such as trione oxime herbicides oraryloxyphenoxypropionic acid herbicides according to classical breedingmethods is SR corn.

The crops which have acquired resistance to acetyl-CoA carboxylaseinhibitors are disclosed in Proceedings of the National Academy ofSciences of the United State of America (Proc. Natl. Acad. Sci. USA),Vol. 87, pp. 7175-7179 (1990), and other publications. Moreover, amutant acetyl-CoA carboxylase that is resistant to acetyl-CoAcarboxylase inhibitors is disclosed in Weed Science, Vol. 53, pp.728-746 (2005), and other publications. Such mutant acetyl-CoAcarboxylase gene is introduced into a crop according to a generecombination technology, or a mutation associated with addition ofresistance is introduced into the acetyl-CoA carboxylase of a crop, soas to produce a crop that is resistant to acetyl-CoA carboxylaseinhibitors.

Moreover, a base substitution mutation-introduced nucleic acid, whichincludes chimeraplasty technology (Gura T. 1999. Repairing the Genome'sSpelling Mistakes. Science 285: 316-318) as a typical example, isintroduced into the cells of a crop, so as to cause a site-directedamino acid substitution mutation to a crop (acetyl-CoAcarboxylase/herbicide target) gene, thereby producing a crop resistantto (acetyl-CoA carboxylase inhibitor/herbicide).

Examples of such crop which has acquired resistance as a result of agene recombination technology include corn varieties resistant toglyphosate and glufosinate. Such corn varieties have already been onsale with product names “RoundupReady” [registered trademark],“LibertyLink” [registered trademark], and the like.

The “crops” include plants which have become able to synthesizeselective toxin and the like that are known in genus Bacillus using agene recombination technology.

Examples of such toxin produced in such genetically modified plantsinclude insecticidal proteins derived from Bacillus cereus and Bacilluspopilliae; insecticidal proteins derived from Bacillus thuringiensis,including δ-endotoxins such as Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab,Cry3A, Cry3Bb1 or Cry9C, VIP1, VIP2, VIP3, VIP3A, or the like;insecticidal proteins derived from nematode; toxins produced by animals,such as scorpion toxin, spider toxin, bee toxin, or insect-specificneurotoxin; toxins of filamentous fungi; plant lectin; agglutinin;protease inhibitors such as a trypsin inhibitor, a serine proteaseinhibitor, patatin, cystatin, or a papain inhibitor;ribosome-inactivating proteins (RIP) such as ricin, corn-RIP, abrin,rufin, sapolin, or briodin; steroid metabolic enzymes such as3-hydroxysteroid oxidase, ecdysteroid-UDP-glucosyltransferase, orcholesterol oxidase; ecdysone inhibitors; HMG-CoA reductase; ion channelinhibitors such as a sodium channel inhibitor or a calcium channelinhibitor; juvenile hormone esterase; diuretic hormone receptors;stilbene synthetase; bibenzyl synthetase; chitinase; and glucanase.

The toxins produced in such genetically modified crops also includehybrid toxins, partially deficient toxins and modified toxins of theabove-described insecticidal proteins. The hybrid toxins are produced bya novel combination of the different domains of such a protein byadopting a recombination technique. As the partially deficient toxin,Cry1Ab, which is deficient in a part of the amino acid sequence, isknown. In the modified toxins, one or more amino acids of a naturaltoxin have been replaced.

Examples of such toxins and genetically modified plants capable ofsynthesizing such toxins are disclosed in EP-A-0374753, WO 93/07278, WO95/34656, EP-A-0427529, EP-A-0451878, WO 03/052073, etc.

The toxins contained in such genetically modified plants impart to theplants, resistance to, particularly, insect pests belonging toColeoptera, insect pests belonging to Diptera, and insect pestsbelonging to Lepidoptera.

Genetically modified plants containing one or more insecticidalinsect-resistant genes and capable of producing one or more toxins havealready been known, and some of them are on the market. As thesegenetically modified plants, there are exemplified YieldGard [registeredtrademark] (a corn variety capable of producing Cry1Ab toxin), YieldGardRootworm [registered trademark] (a corn variety capable of producingCry3Bbl toxin), YieldGard Plus [registered trademark] (a corn varietycapable of producing Cry1 Ab and Cry3Bbl toxins), Herculex I [registeredtrademark] (a corn variety capable of producing phosphinotrysinN-acetyltransferase (PAT) for imparting resistance to Cry1Fa2 toxin andGlufosinate), NuCOTN33B [registered trademark] (a cotton variety capableof producing Cry1Ac toxin), Bollgard I [registered trademark] (a cottonvariety capable of producing Cry1Ac toxin), Bollgard II [registeredtrademark] (a cotton variety capable of producing Cry1Ac and Cry2Abtoxins), VIPCOT [registered trademark] (a cotton variety capable ofproducing VIP toxin), NewLeaf [registered trademark] (a potato varietycapable of producing Cry3A toxin), NatureGard [registered trademark],Agrisure [registered trademark], GT Advantage (GA21 glyphosate-resistantproperties), Agrisure [registered trademark], CB Advantage (Bt11 cornborer (CB) properties), and Protecta [registered trademark].

The “crops” also include crops having an ability to produce ananti-pathogenic substance having selective action which has beenimparted by a gene recombination technology.

Examples of such anti-pathogenic substance produced in geneticallymodified plants include: ion channel inhibitors such as sodium channelinhibitors and calcium channel inhibitors (for example, KP1, KP4 and KP6toxins produced by viruses are known); stilbene synthases; bibenzylsynthases; chitinase; glucanase; PR proteins (PRPs, EP 0392225 A); andanti-pathogenic substances produced by microorganisms, such as peptideantibiotics, antibiotics having a heterocyclic ring, and protein factorsassociated with resistance to plant diseases (disclosed in WO03/000906). Such anti-pathogenic substances and genetically modifiedplants producing such substances are disclosed in EP 0392225 A, WO95/33818, EP 0353191 A, etc.

The “crops” also include crops having useful properties such as an oilingredient-modifying property or an amino acid content-increasingproperty which has been imparted by a gene recombination technology.Examples of such crop having useful properties include: VISTIVE[registered trademark] (a low linoleic acid soybean containing a reducedamount of linoleic acid); and high-lysine (high-oil) corn (a corncontaining an increased amount of lysine or oil).

The crops further include stack varieties, in which a plurality of theclassical herbicide properties, a herbicide resistance gene, aninsecticidal insect pest resistance gene, an anti-pathogenicsubstance-producing gene, and useful properties such as an oilingredient-modifying property or an amino acid content-increasingproperty are combined.

When the present active compound is used to control arthropod pests thatreside in a house (e.g. a fly, a mosquito, and a cockroach), the amountapplied is generally 0.01 to 1,000 mg per m² of area to be treated, inthe case of applying it to a floor. In the case of applying the activecompound to a space, the amount applied is generally 0.01 to 500 mg perm³ of space to be treated. When the present active compound isformulated to an emulsion, a wettable powder, a flowable agent, etc., itis generally diluted with water to a concentration of 0.1 to 1,000 ppm.When the active compound is in the form of an oil agent, an aerosol, afumigant, a toxic bait, etc., it is applied as it is.

EXAMPLES

Hereinafter, the present invention is described in more detail withreference to Production Examples, Reference Production Examples, andTest Examples. However, the present invention is not necessarily limitedto these Examples.

Production Example 1

A mixture of 1.2 g of 2-amino-4-propylphenol, 0.98 g of isonicotinicacid and 32.8 g of polyphosphoric acid was stirred while heating at 190°C. for five hours. The mixture was cooled to room temperature and thenpoured into an ice-cooled aqueous solution of sodium hydroxide, followedby extraction with ethyl acetate three times. The combined organiclayers were washed with water and a saturated sodium chloride solution,and dried over magnesium sulfate. Activated carbon was added thereto,which was filtered through Celite™. The filtrate was concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.72 g of 5-propyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 1”).

Active Compound 1

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.6, 1.7 Hz, 2H), 8.08 (dd, J=4.5, 1.7 Hz,2H), 7.62-7.60 (m, 1H), 7.54-7.50 (m, 1H), 7.27-7.23 (m, 1H), 2.74 (t,J=7.5 Hz, 2H), 1.76-1.66 (m, 2H), 1.31 (t, J=7.5 Hz, 3H)

Production Example 2

Production Example 2 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-methylphenol instead of2-amino-4-propylphenol to give 5-methyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 2”).

Active Compound 2

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.5, 1.6 Hz, 2H), 8.07 (dd, J=4.5, 1.6 Hz,2H), 7.62-7.59 (m, 1H), 7.52-7.48 (m, 1H), 7.25-7.22 (m, 1H), 2.51 (s,3H)

Production Example 3

Production Example 3 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-ethylphenol instead of2-amino-4-propylphenol to give 5-ethyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 3”).

Active Compound 3

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.6, 1.7 Hz, 2H), 8.07 (dd, J=4.4, 1.7 Hz,2H), 7.64-7.62 (m, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 1.7 Hz,1H), 2.80 (q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H)

Production Example 4

Production Example 4 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-butylphenol instead of2-amino-4-propylphenol to give 5-butyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 4”).

Active Compound 4

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.4, 1.7 Hz, 2H), 8.08 (dd, J=4.6, 1.7 Hz,2H), 7.62-7.61 (m, 1H), 7.53-7.50 (m, 1H), 7.27-7.23 (m, 1H), 2.76 (t,J=7.6 Hz, 2H), 1.71-1.62 (m, 2H), 1.44-1.33 (m, 2H), 0.95 (t, J=7.3 Hz,3H)

Production Example 5

Production Example 5 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-isopropylphenol instead of2-amino-4-propylphenol to give 5-isopropyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 5”).

Active Compound 5

¹H-NMR (CDCl₃) δ: 8.82 (dd, J=4.5, 1.6 Hz, 2H), 8.08 (dd, J=4.5, 1.6 Hz,2H), 7.68 (d, J=1.7 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.4,1.8 Hz, 1H), 3.11-3.04 (m, 1H), 1.33 (d, J=6.8 Hz, 6H)

Production Example 6

Production Example 6 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-tert-butylphenol instead of2-amino-4-propylphenol to give 5-tert-butyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 6”).

Active Compound 6

¹H-NMR (CDCl₃) δ: 8.83-8.80 (m, 2H), 8.09-8.06 (m, 2H), 7.86-7.83 (m,1H), 7.56-7.48 (m, 2H), 1.41 (s, 9H)

Production Example 7

Production Example 7 was carried out according to the same manner as inProduction Example 1, using 2-amino-5-methylphenol instead of2-amino-4-propylphenol to give 6-methyl-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 7”).

Active Compound 7

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.5, 1.6 Hz, 2H), 8.07 (dd, J=4.5, 1.6 Hz,2H), 7.69 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=8.3 Hz, 1H), 2.53(s, 3H)

Production Example 8

A mixture of 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide,15 ml of carbon tetrachloride, 3.55 g of triphenylphosphine and 1.37 gof triethylamine was heated to reflux for three hours. The mixture wascooled to room temperature, and then water was poured into the mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with a saturated sodium chloride solution, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 0.30 gof 6-tert-butyl-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred toas “active compound 8”).

Active Compound 8

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.6, 1.7 Hz, 2H), 8.07 (dd, J=4.4, 1.7 Hz,2H), 7.74 (d, J=8.3

Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.48 (dd, J=8.5, 1.7 Hz, 1H), 1.41 (s,9H)

Production Example 9

Production Example 9 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-chlorophenol instead of2-amino-4-propylphenol to give 5-chloro-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 9”).

Active Compound 9

¹H-NMR (CDCl₃) δ: 8.84 (dd, J=4.4, 1.7 Hz, 2H), 8.07 (dd, J=4.4, 1.7 Hz,2H), 7.80 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8,2.0 Hz, 1H)

Production Example 10

Production Example 10 was carried out according to the same manner as inProduction Example 1, using 2-amino-4-bromophenol instead of2-amino-4-propylphenol to give 5-bromo-2-(pyridin-4-yl)-benzoxazole(hereinafter, referred to as “active compound 10”).

Active Compound 10

¹H-NMR (CDCl₃) δ: 8.83 (dd, J=4.4, 1.7 Hz, 2H), 8.07 (dd, J=4.4, 1.6 Hz,2H), 7.96 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.6, 1.8 Hz, 1H), 7.51 (dd,J=8.5 Hz, 1H)

Production Example 11

To a mixture of 1.17 g of N-(2-hydroxy-5-methoxyphenyl)isonicotinamide,1.26 g of triphenylphosphine and 25 ml of tetrahydrofuran, a mixture of0.85 g diethyl azodicarboxylate and 5 ml of tetrahydrofuran was addeddropwise. The mixture was warmed to room temperature and stirred forfour hours. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The combined organic layers were washedwith water and a saturated sodium chloride solution, and dried overmagnesium sulfate. Activated carbon was added thereto, which wasfiltered through Celite™. The filtrate was concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.11 g of 5-methoxy-2-(pyridin-4-yl)-benzoxazole (hereinafter,referred to as “active compound 11”).

Active Compound 11

¹H-NMR (CDCl₃) δ: 8.81 (dd, J=4.4, 1.7 Hz, 2H), 8.07-8.05 (m, 2H), 7.51(d, J=9.0 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.04 (dd, J=9.0, 2.7 Hz, 1H),3.89 (s, 3H)

Production Example 12

To a mixture of 1.96 g ofN-[5-(trifluoromethoxy)-2-hydroxyphenyl]isonicotinamide, 35 ml oftetrahydrofuran and 1.73 g of triphenylphosphine, a mixture of 1.26 g ofdiethyl azodicarboxylate and 5 ml of THF was added dropwise at roomtemperature. The resultant mixture was stirred at room temperature fortwo hours. To the mixture, 1.73 g of triphenylphosphine and 3.15 g of40% toluene solution of diethyl azodicarboxylate were added and stirredfor one hour. Furthermore, to the mixture, 0.58 g of triphenylphosphineand 1.05 g of 40% toluene solution of diethyl azodicarboxylate wereadded and stirred for one hour. The mixture solution was poured intowater, followed by extraction with ethyl acetate. The combined organiclayers were washed with water and a saturated sodium chloride solution,and dried over magnesium sulfate. The reaction mixture was concentrated.The residue was subjected to silica gel column chromatography to give2-(pyridin-4-yl)-5-(trifluoromethoxy)benzoxazole (hereinafter, referredto as “active compound 12”).

Active Compound 12

¹H-NMR (CDCl₃) δ: 8.86-8.84 (m, 2H), 8.10-8.07 (m, 2H), 7.73-7.70 (m,1H), 7.64 (d, J=8.8 Hz, 1H), 7.35-7.30 (m, 1H)

Production Example 13

To a mixture of 1.69 g ofN-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide, 25 ml oftetrahydrofuran and 2.36 g of triphenylphosphine, 3.91 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. After 1.3 hours, 0.6 g of triphenylphosphine and 1.0 g of40% toluene solution of diethyl azodicarboxylate were added and stirredfor further 40 minutes. Water was poured into the mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with water and a saturated sodium chloride solution, dried oversodium sulfate, and then concentrated under reduced pressure. Theresidue was washed with diethyl ether, and 10 ml of methanol and 10 mlof 1 M aqueous solution of sodium hydroxide were added and stirred fortwo hours at room temperature. After concentrated hydrochloric acid wasadded to the reaction mixture while ice-cooling so as to make it acidic,the reaction mixture was washed with ethyl acetate. To the aqueouslayer, 1 M aqueous solution of sodium hydroxide was added so as to makethe solution alkaline, followed by extraction with ethyl acetate twice.The combined organic layers were washed with water and a saturatedsodium chloride solution, and dried over magnesium sulfate and thenconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.44 g of2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referredto as “active compound 13”).

Active Compound 13

¹H-NMR (CDCl₃) δ: 8.86 (dd, J=4.4, 1.7 Hz, 2H), 8.13-8.09 (m, 3H), 7.75(d, J=8.5 Hz, 1H), 7.72 (dd, J=8.7, 1.6 Hz, 1H)

Production Example 14

To a mixture of 0.47 g of2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform,0.64 g of 65% m-chloroperbenzoic acid was added while ice-cooling. Thereaction mixture was stirred while ice-cooling for 30 minutes, and thenstirred at room temperature for 1.5 hours. The reaction mixture wasdiluted with chloroform, and washed with 5% aqueous solution of sodiumhydroxide and a saturated sodium chloride solution. Organic layers weredried over anhydrous sodium sulfate, and then concentrated under reducedpressure to give 0.39 g of4[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter,referred to as “active compound 14”).

Active Compound 14

¹H-NMR (CDCl₃) δ: 8.34-8.31 (m, 2H), 8.13-8.10 (m, 2H), 8.08 (s, 1H),7.73-7.68 (m, 2H)

Production Example 15

A mixture of 0.8 g ofN-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide, 15 ml of carbontetrachloride, 2.23 g of triphenylphosphine and 0.86 g of triethylaminewas heated to reflux for five hours. The mixture was cooled to roomtemperature. Then, water was poured into the mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with water and a saturated sodium chloride solution, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 0.25 gof 2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 15”).

Active Compound 15

¹H-NMR (CDCl₃) δ: 8.87 (dd, J=4.5, 1.6 Hz, 2H), 8.11 (dd, J=4.4, 1.5 Hz,2H), 7.95-7.91 (m, 2H), 7.72-7.68 (m, 1H)

Production Example 16

To a mixture of 1.34 g ofN-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide,10 ml of tetrahydrofuran and 1.07 g of triphenylphosphine, 2.67 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. After 30 minutes, 1.07 g of triphenylphosphine was added,2.67 g of 40% toluene solution of diethyl azodicarboxylate was addeddropwise thereto and stirred for further two hours. Water was addedthereto, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyand the resultant solid was recrystallized to give 0.14 g of5,5,7,7-tetrafluoro-2-pyridin-4-yl-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 16”).

Active Compound 16

¹H-NMR (CDCl₃) δ: 8.91 (dd, J=4.4, 1.7 Hz, 2H), 8.12 (dd, J=4.5, 1.6 Hz,2H), 8.08 (s, 1H), 7.91 (s, 1H)

Production Example 17

A mixture of 0.35 g of3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide, 5 mlof carbon tetrachloride, 0.78 g of triphenylphosphine and 0.30 g oftriethylamine was heated to reflux for three hours. The mixture wascooled to room temperature, and then water was added to the mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with a saturated sodium chloride solution, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.18 g of2-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 17”).

Active Compound 17

¹H-NMR (CDCl₃) δ: 8.72 (s, 2H), 8.21 (s, 1H), 7.79-7.77 (m, 2H)

Production Example 18

To a mixture of 0.71 g of2-(3-chloropyridin-4-yl)methylideneamino-4-(trifluoromethyl)phenol and10 ml of methanol, 0.80 g of iodobenzene diacetate was added at roomtemperature and stirred for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure, and then water was added to thereaction mixture, followed by extraction with ethyl acetate. Organiclayers were washed with a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.14 g of2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 18”).

Active Compound 18

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.20-8.18 (m,1H), 8.10 (d, J=5.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.75 (dd, J=8.5,1.2 Hz, 1H)

Production Example 19

To a mixture of 1.74 g of3-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 15 mlof tetrahydrofuran and 1.73 g of triphenylphosphine, 2.87 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred at 50° C. for 30 minutes.After 30 minutes, 0.26 g of triphenylphosphine and 0.43 g of 40% toluenesolution of diethyl azodicarboxylate were added and the reaction mixturewas stirred at 50° C. for one hour. The reaction mixture was cooled toroom temperature and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 1.44 gof active compound 18.

Production Example 20

To a mixture of 0.45 g of2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml ofchloroform, 0.53 g of 65% m-chloroperbenzoic acid was added whileice-cooling. The reaction mixture was stirred at room temperature for5.5 hours, and was then diluted with chloroform, and washed with 5%aqueous solution of sodium hydroxide and a saturated sodium chloridesolution, sequentially. Organic layers were dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.25 g of3-chloro-4[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide(hereinafter, referred to as “active compound 19”).

Active Compound 19

¹H-NMR (CDCl₃) δ: 8.40 (d, J=1.3 Hz, 1H), 8.21 (dd, J=7.1, 1.5 Hz, 1H),8.17-8.14 (m, 2H), 7.77-7.72 (m, 2H)

Production Example 21

To a mixture of 0.49 g of2-(3-chloropyridin-4-yl)methylideneamino-4-tert-butylphenol and 10 ml ofmethanol, 0.57 g of iodobenzene diacetate was added at room temperatureand stirred for two hours. The reaction mixture was concentrated, andthen water was added thereto, followed by extraction with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution sequentially,and dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.21 g of2-(3-chloropyridin-4-yl)-5-tert-butylbenzoxazole (hereinafter, referredto as “active compound 20”).

Active Compound 20

¹H-NMR (CDCl₃) δ: 8.81 (s, 1H), 8.65 (d, J=5.1 Hz, 1H), 8.07 (d, J=5.1Hz, 1H), 7.92-7.91 (m 1H), 7.57 (dd, J=8.8, 0.7 Hz, 1H), 7.53 (dd,J=8.8, 1.8 Hz, 1H), 1.41 (s, 9H)

Production Example 22

To a mixture of 0.77 g of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 20 mlof tetrahydrofuran and 0.80 g of triphenylphosphine, 1.32 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature, and the mixture solution was stirred for 1.5 hours at roomtemperature and then 1.5 hours at 60° C. The reaction mixture was cooledto room temperature, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 0.60 gof 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 21”).

Active Compound 21

¹H-NMR (CDCl₃) δ: 8.63 (d, J=5.3, 1H), 8.17-8.12 (m, 2H), 8.05-8.03 (m,1H), 7.77-7.72 (m, 2H)

Production Example 23

To a mixture of 0.40 g of2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml ofchloroform, 0.53 g of 65% m-chloroperbenzoic acid was added whileice-cooling. The reaction mixture was stirred while ice-cooling for 30minutes, then stirred at room temperature for three hours, and thenstirred while heating at 50° C. for 1.5 hours. To the mixture, 0.53 g of65% m-chloroperbenzoic acid and 2 ml of chloroform were added andstirred while heating at 60° C. for five hours. The reaction mixture wascooled to room temperature, then diluted with ethyl acetate, and washedwith 5% aqueous solution of sodium hydroxide and a saturated sodiumchloride solution, sequentially. The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure togive 0.38 g of 2-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridineN-oxide (hereinafter, referred to as “active compound 22”).

Active Compound 22

¹H-NMR (CDCl₃) δ: 8.45 (d, J=7.1 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H),8.10-8.08 (m, 1H), 8.04 (dd, J=7.1, 2.4 Hz, 1H), 7.73-7.72 (m, 2H)

Production Example 24

To a mixture of 0.38 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-methylisonicotinamide, 5 ml oftetrahydrofuran and 0.42 g of triphenylphosphine, 0.69 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature and stirred while heating at 60° C. After three hours, 5 mlof 10% aqueous solution of sodium hydroxide was added and stirred whileheating at 60° C. for two hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 0.29 gof 2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 23”).

Active Compound 23

¹H-NMR (CDCl₃) δ: 8.69 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.16-8.14 (m,1H), 8.04 (d, J=5.3 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.8,1.2 Hz, 1H), 2.83 (s, 3H)

Production Example 25

To a mixture of 0.20 g of2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml ofchloroform, 0.30 g of 65% m-chloroperbenzoic acid was added whileice-cooling. The reaction mixture was stirred at room temperature forthree hours, then diluted with ethyl acetate, and washed with 5% aqueoussolution of sodium hydroxide and a saturated sodium chloride solution,sequentially. The organic layer was dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give 0.17 g of3-methyl-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide(hereinafter, referred to as “active compound 24”).

Active Compound 24

¹H-NMR (CDCl₃) δ: 8.22-8.21 (m, 1H), 8.19-8.16 (m, 1H), 8.12-8.09 (m,2H), 7.72-7.69 (m, 2H), 2.81 (s, 3H)

Production Example 26

To a mixture of 0.51 g of3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml oftetrahydrofuran and 0.53 g of triphenylphosphine, 0.89 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred while heating at 50° C.for 1.5 hours. The reaction mixture was cooled to room temperature, andthen concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography to give 0.46 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 25”).

Active Compound 25 ¹H-NMR (CDCl₃) δ: 8.76 (d, J=2.4 Hz, 1H), 8.66 (d,J=0.6 Hz, 1H), 8.17 (m, 1H), 8.15-8.12 (m, 1H), 7.78 (d, J=8.8 Hz, 1H),7.75 (dd, J=8.8, 1.3 Hz, 1H) Production Example 27

To a mixture of 0.34 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 6 ml ofchloroform, 0.48 g of 65% m-chloroperbenzoic acid was added at roomtemperature. The solution was stirred while heating at 50° C. for 1.5hours. The reaction mixture was cooled to room temperature, and dilutedwith ethyl acetate, and then washed with a saturated aqueous solution ofsodium hydrogencarbonate twice and a saturated sodium chloride solutiononce, sequentially. The organic layer was dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.23 g of3-fluoro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide(hereinafter, referred to as “active compound 26”).

Active Compound 26

¹H-NMR (CDCl₃) δ: 8.32-8.29 (m, 1H), 8.17-8.12 (m, 3H), 7.76-7.71 (m,2H)

Production Example 28

To a mixture of 0.29 g of3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 4 ml oftetrahydrofuran and 0.25 g of triphenylphosphine, 0.42 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred while heating at 50° C.for 1.5 hours. The reaction mixture was cooled to room temperature, andthen concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography to give 0.24 g of2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 27”).

Active Compound 27

¹H-NMR (CDCl₃) δ: 9.00 (s, 1H), 8.73 (d, J=4.9 Hz, 1H), 8.20 (s, 1H),8.06 (d, J=4.9 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H)

Production Example 29

To a mixture of 0.50 g of2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml ofchloroform, 0.58 g of 65% m-chloroperbenzoic acid was added. Thereaction mixture was stirred while heating at 50° C. for 1.5 hours. Thereaction mixture was cooled to room temperature, then diluted with ethylacetate, and washed with a saturated aqueous solution of sodiumhydrogencarbonate (twice) and a saturated sodium chloride solution,sequentially. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography to give 0.37 g of3-bromo-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide(hereinafter, referred to as “active compound 28”).

Active Compound 28

¹H-NMR (CDCl₃) δ: 8.56 (d, J=1.7 Hz, 1H), 8.24 (dd, J=7.1, 1.7 Hz, 1H),8.16 (s, 1H), 8.13 (d, J=7.1 Hz, 1H), 7.76-7.72 (m, 2H)

Production Example 30

To a mixture of 1.81 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-iodoisonicotinamide, 20 ml oftetrahydrofuran and 1.34 g of triphenylphosphine, 2.22 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred while heating at 50° C.for one hour. The reaction mixture was cooled to room temperature, andthen the reaction mixture was concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 1.40 gof 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 29”).

Active Compound 29

¹H-NMR (CDCl₃) δ: 9.26 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.21 (s, 1H),8.01 (d, J=5.1 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H)

Production Example 31

To a mixture of 0.30 g of2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml ofchloroform, 0.26 g of 65% m-chloroperbenzoic acid was added whileice-cooling. The reaction mixture was stirred at room temperature for 30minutes. The reaction mixture was stirred while heating at 50° C. forone hour. Then, 0.20 g of 65% m-chloroperbenzoic acid was added theretoand stirred while heating at 50° C. for further two hours. The reactionmixture was cooled to room temperature, and then diluted with ethylacetate, and washed with a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution,sequentially. The organic layer was dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The residue was subjectedto silica gel column chromatography to give 0.09 g of3-iode-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide(hereinafter, referred to as “active compound 30”).

Active Compound 30

¹H-NMR (CDCl₃) δ: 8.83 (d, J=1.7 Hz, 1H), 8.25 (dd, J=7.1, 1.7 Hz, 1H),8.18-8.15 (m, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.75-7.72 (m, 2H)

Production Example 32

A mixture of 0.39 g of2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of copper(I) cyanide and 2 ml of 1-methyl-2-pyrrolidinone was stirred whileheating at 80° C. for 2 hours. Water and ethyl acetate were poured intothe reaction mixture, which was filtered through Celite™. The resultantfiltrate was washed with a saturated sodium chloride solution, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give0.11 g of 2-(3-cyanopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 31”).

Active Compound 31

¹H-NMR (CDCl₃) δ: 9.14 (s, 1H), 9.02 (d, J=5.4 Hz, 1H), 8.29 (d, J=5.1Hz, 1H), 8.25-8.22 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8, 1.3Hz, 1H)

Production Example 33

To a mixture of 0.78 g of2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofphenylboronic acid, 5 ml of tetrahydrofuran and 0.14 g ofdichlorobis(triphenylphosphine)palladium (II), 3 ml of 10% aqueoussolution of sodium hydroxide was added and heated to reflux for threehours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate twice. The combined organic layers were washed withwater and a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.18 g of2-(3-phenyl pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 32”).

Active Compound 32

¹H-NMR (CDCl₃) δ: 8.81 (d, J=5.1 Hz, 1H), 8.80 (s, 1H), 8.05-8.02 (m,2H), 7.62-7.59 (m, 1H), 7.45-7.38 (m, 4H), 7.35-7.30 (m, 2H)

Production Example 35

A mixture of 1.17 g of2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.40 g of(trimethylsilyl)acetylene, 0.03 g of copper (I) iodide, 0.11 g ofdichlorobis(triphenylphosphine)palladium (II), 2.5 ml of triethylamineand 10 ml of tetrahydrofuran was stirred while heating at 50° C. for twohours. The reaction solution was cooled to room temperature, to whichtert-butyl methyl ether was added. The reaction mixture was washed witha saturated aqueous solution of sodium hydrogencarbonate and a saturatedsodium chloride solution sequentially. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give0.50 g of 5-(trifluoromethyl)2-[3-(trimethylsilyl)ethynyl-4-yl]-benzoxazole.

¹H-NMR (CDCl₃) δ: 8.93 (d, J=0.7 Hz, 1H), 8.71 (d, J=5.3 Hz, 1H),8.13-8.11 (m, 1H), 8.10 (dd, J=5.3, 0.7 Hz, 1H), 7.73-7.72 (m, 2H), 0.35(s, 9H)

To a mixture of 0.74 g of5-(trifluoromethyl)-2-[3-(trimethylsilyl)ethynyl-4-yl]-benzoxazole and 6ml of methanol, 0.20 g of potassium carbonate was added. The reactionmixture was stirred at room temperature for one hour. Water was added tothe reaction mixture, which was extracted with ethyl acetate. Theorganic layer was washed with a saturated sodium chloride solution, thendried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.46 g of2-(3-ethynylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 34”).

Active Compound 34

¹H-NMR (CDCl₃) δ: 8.97 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.19-8.17 (m,1H), 8.10 (d, J=5.1 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.5,1.2 Hz, 1H), 3.63 (s, 1H)

Production Example 36

A mixture of 0.34 g of2-(3-ethynylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of 5%palladium on carbon and 8 ml of ethyl acetate was stirred under aboutone atmosphere of hydrogen at room temperature for two hours. Thereaction mixture was filtered through Celite™. The filtrate wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.33 g of2-(3-ethylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 35”).

Active Compound 35

¹H-NMR (CDCl₃) δ: 8.71 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.16-8.14 (m,1H), 8.01 (d, J=5.1 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8,1.3 Hz, 1H), 3.29 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H)

Production Example 37

To a mixture of 1.78 g of3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide,20 ml of tetrahydrofuran and 1.29 g of triphenylphosphine, 2.15 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred at room temperature forone hour and then stirred while heating at 50° C. for 30 minutes. Thereaction mixture was cooled to room temperature, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 0.69 g of 2-(3-tert-butoxycarbonylaminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred toas “active compound 36”).

Active Compound 36

¹H-NMR (CDCl₃) δ: 10.57 (s, 1H), 9.88 (s, 1H), 8.45 (d, J=5.1 Hz, 1H),8.17 (s, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.78-7.73 (m, 2H), 1.62 (s, 9H)

Production Example 38

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of methanol was stirred while heating at60° C. for two hours. The reaction mixture was concentrated underreduced pressure. Water was added thereto, which followed by extractionwith ethyl acetate twice. The combined organic layers were washed withwater and a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.21 g of2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 37”).

Active Compound 37

¹H-NMR (CDCl₃) δ: 8.60 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 8.16-8.14 (m,1H), 8.02 (d, J=4.9 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5,1.1 Hz, 1H), 4.16 (s, 3H)

Production Example 39

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.15 g ofphenol, 0.55 g of potassium carbonate and 2 ml of DMF was stirred atroom temperature for one hour, and then stirred while heating at 50° C.for four hours. The reaction mixture was cooled to room temperature, andthen water was added to the reaction mixture, followed by extractionwith ethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.24 g of2-(3-phenoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 38”).

Active Compound 38

¹H-NMR (CDCl₃) δ: 8.57 (d, J=4.9 Hz, 1H), 8.47 (s, 1H), 8.14 (d, J=4.9Hz, 1H), 8.11 (s, 1H), 7.69-7.65 (m, 2H), 7.41-7.37 (m, 2H), 7.20-7.16(m, 1H), 7.13-7.09 (m, 2H)

Production Example 40

A mixture of 0.06 g of 55% sodium hydride (in oil) and 2 ml of DMF wasstirred at room temperature. To the mixture, a mixture solution of 0.13g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixturesolution was stirred at the same temperature for 15 minutes, and then0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole wasstirred at room temperature for one hour. Water was added to thereaction mixture, which followed by extraction with ethyl acetate twice.The combined organic layers were washed with a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 0.27 g of2-[3-(2,2,2-trifluoroethyl)oxypyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 39”).

Active Compound 39

¹H-NMR (CDCl₃) δ: 8.61 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 8.15-8.14 (m,1H), 8.11 (d, J=5.1 Hz, 1H), 7.76-7.71 (m, 2H), 4.67 (q, J=8.0 Hz, 2H)

Production Example 41

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g ofmethyl mercaptan sodium salt and 2 ml of DMF was stirred while heatingat 50° C. for two hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate. The organic layer was washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The resultant residuewas subjected to silica gel column chromatography to give 0.21 g of2-[3-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 40”).

Active Compound 40

¹H-NMR (CDCl₃) δ: 8.68 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 8.22-8.20 (m,1H), 8.02 (d, J=5.1 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.71 (dd, J=8.8,1.4 Hz, 1H), 2.68 (s, 3H)

Production Example 42

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.20 g of ethylmercaptan sodium salt and 2 ml of DMF was stirred at room temperaturefor one hour. Water was added to the reaction mixture, and was extractedwith ethyl acetate. The organic layer was washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.28 g of 2-(3-ethylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred toas “active compound 41”).

Active Compound 41

¹H-NMR (CDCl₃) δ: 8.72 (s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.21 (s, 1H),8.01 (d, J=5.1 Hz, 1H), 7.76-7.70 (m, 2H), 3.20 (q, J=7.5 Hz, 2H), 1.48(t, J=7.5 Hz, 3H)

Production Example 43

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.15 g of1-propanethiol, 0.40 g of potassium carbonate and 2 ml of DMF wasstirred while heating at 50° C. for one hour. The reaction mixture wascooled to room temperature, and then water was added to the reactionmixture, which was extracted with ethyl acetate. The organic layer waswashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.30 g of2-(3-propylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 42”).

Active Compound 42

¹H-NMR (CDCl₃) δ: 8.72 (s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.23-8.21 (m,1H), 8.01 (d, J=5.1 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.8,1.5 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 1.87-1.80 (m, 2H), 1.13 (t, J=7.6Hz, 3H)

Production Example 44

To a mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g ofpotassium carbonate and 2 ml of DMF, a mixture of 0.15 g of2-propanethiol and 0.5 ml of DMF was added. The reaction mixture wasstirred while heating at 60° C. for two hours. The reaction mixture wascooled to room temperature, and then water was added to the reactionmixture, which was extracted with ethyl acetate. The organic layer waswashed with 5% aqueous solution of potassium carbonate and a saturatedsodium chloride solution, sequentially, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.26 g of2-(3-isopropylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 43”).

Active Compound 43

¹H-NMR (CDCl₃) δ: 8.79 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.22-8.20 (m,1H), 7.99 (d, J=5.1 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.8,1.4 Hz, 1H), 3.78 (sep, J=6.6 Hz, 1H), 1.45 (d, J=6.6 Hz, 6H)

Production Example 45

Production Example 45 was carried out according to the same manner as inProduction Example 43, using tert-butyl mercaptan instead of2-propanethiol. Thus,2-(3-tert-butylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 44”) was obtained.

Active Compound 44

¹H-NMR (CDCl₃) δ: 8.99 (d, J=0.7 Hz, 1H), 8.77 (d, J=5.1 Hz, 1H),8.18-8.16 (m, 1H), 7.93 (dd, J=5.1, 0.7 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H),7.73 (dd, J=8.8, 1.5 Hz, 1H), 1.24 (s, 9H)

Production Example 46

Production Example 46 was carried out according to the same manner as inProduction Example 43, using 1-pentanethiol instead of 2-propanethiol.Thus, 2-(3-pentylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 45”) was obtained.

Active Compound 45

¹H-NMR (CDCl₃) δ: 8.72 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.23-8.21 (m,1H), 8.00 (d, J=5.1, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.8, 1.6Hz, 1H), 3.13 (t, J=7.6 Hz, 2H), 1.81 (m, 2H), 1.50 (m, 2H), 1.38 (m,2H), 0.92 (t, J=7.5 Hz, 3H)

Production Example 47

To a mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g ofpotassium carbonate and 2 ml of DMF, 0.15 g of2,2,2-trifluoroethanethiol was added. The reaction mixture was stirredat room temperature for 1.2 hours. Water was added to reaction mixture,which followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.32 g of2-[3-(2,2,2-trifluoroethylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 46”).

Active Compound 46

¹H-NMR (CDCl₃) δ: 8.94 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.22-8.21 (m,1H), 8.06 (d, J=5.1 Hz, 1H), 7.78-7.73 (m, 2H), 3.76 (q, J=9.5 Hz, 2H)

Production Example 48

Production Example 48 was carried out according to the same manner as inProduction Example 43 except for using benzyl mercaptan instead of2-propanethiol. Thus,2-(3-benzylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 47”) was obtained.

Active Compound 47

¹H-NMR (CDCl₃) δ: 8.75 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 8.19-8.18 (m,1H), 8.00 (dd, J=5.2, 0.8 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.70 (dd,J=8.8, 1.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.35-7.27 (m, 3H), 4.36 (s, 2H)

Production Example 49

Production Example 49 was carried out according to the method as inProduction Example 43 except for using 4-chlorobenzyl mercaptan insteadof 2-propanethiol. Thus,2-[3-(4-chlorobenzylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 48”) was obtained.

Active Compound 48

¹H-NMR (CDCl₃) δ: 8.71 (s, 1H), 8.58 (d, J=5.1 Hz, 1H), 8.20-8.18 (m,1H), 8.00 (d, J=5.1 Hz, 1H), 7.75-7.70 (m, 2H), 7.35-7.32 (m, 2H),7.29-7.26 (m, 2H), 4.32 (s, 2H)

Production Example 50

To a mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.40 g ofpotassium carbonate and 2 ml of DMF, a mixture of 0.17 g of thiophenoland 0.5 ml of DMF was added. The reaction mixture was stirred at roomtemperature for one hour. Water was added to the reaction mixture, whichwas extracted with ethyl acetate. The organic layer was washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.30 g of2-[3-(phenylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 49”).

Active Compound 49

¹H-NMR (CDCl₃) δ: 8.51 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H),8.02 (d, J=5.1 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.74 (dd, J=8.8, 1.4 Hz,1H), 7.65-7.61 (m, 2H), 7.48-7.45 (m, 3H)

Production Example 51

Production Example 51 was carried out according to the same manner as inProduction Example 50 except for using 4-chlorothiophenol instead ofthiophenol. Thus,2-[3-(4-chloro-phenylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 50”) was obtained.

Active Compound 50

¹H-NMR (CDCl₃) δ: 8.54 (d, J=5.1 Hz, 1H), 8.23-8.22 (m, 1H), 8.20 (s,1H), 8.03 (d, J=5.1 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.74 (dd, J=8.8,1.2 Hz, 1H), 7.57-7.54 (m, 2H), 7.46-7.43 (m, 2H)

Production Example 53

A mixture of 1.41 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.85 g ofphthalimide potassium and 8 ml of DMF was stirred while heating at 120°C. After six hours, 0.92 g of phthalimide potassium was added andstirred while heating at 140° C. for further one hour. The reactionmixture was cooled to room temperature, and then water was added to thereaction mixture, which followed by extraction with ethyl acetate twice.The combined organic layers were washed with water and a saturatedsodium chloride solution, sequentially, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 1.26 g ofN-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide.

¹H-NMR (CDCl₃) δ: 8.95 (d, J=5.1 Hz, 1H), 8.82 (s, 1H), 8.27 (d, J=5.1Hz, 1H), 8.04-7.99 (m, 2H), 7.92-7.88 (m, 2H), 7.73-7.70 (m, 1H), 7.64(dd, J=8.8, 1.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H)

To a mixture of 0.41 g ofN-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide and 5ml of ethanol, 0.3 ml of hydrazine monohydrate was added and stirred atroom temperature for 1.5 hours. To the reaction mixture, ethanol wasadded and filtrated, and the filtrate was concentrated. The residue wasdiluted with ethyl acetate, and washed with water and then with asaturated sodium chloride solution. The organic layer was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.19 g of 2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 52”).

Active Compound 52

¹H-NMR (CDCl₃) δ: 8.34 (d, J=0.5 Hz, 1H), 8.08-8.06 (m, 2H), 7.83 (d,J=5.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.68 (dd, J=8.8, 1.5 Hz, 1H),6.14 (br s, 2H)

Production Example 54

A mixture of 0.31 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g ofpyrrolidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirredwhile heating at 60° C. for one hour. The reaction mixture was cooled toroom temperature, and then water was added to the reaction mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.37 g of2-[3-(pyrrolidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 53”).

Active Compound 53

¹H-NMR (CDCl₃) δ: 8.40 (s, 1H), 8.10 (d, J=4.9 Hz, 1H), 8.09-8.07 (m,1H), 7.71 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.6, 1.7 Hz, 1H), 7.56 (d,J=5.1 Hz, 1H), 3.28-3.24 (m, 4H), 1.97-1.93 (m, 4H)

Production Example 55

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.17 g ofpiperidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirredwhile heating at 50° C. for two hours, and then at 80° C. for 1.3 hours.Water was added to the reaction mixture, followed by extraction withethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.34 g of2-[3-(piperidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 54”).

Active Compound 54

¹H-NMR (CDCl₃) δ: 8.54 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 8.12-8.11 (m,1H), 7.89 (d, J=5.1 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.69 (dd, J=8.8,1.6 Hz, 1H), 3.11-3.09 (m, 4H), 1.81-1.75 (m, 4H), 1.66-1.59 (m, 2H)

Production Example 56

Production Example 56 was carried out according to the same manner as inProduction Example 55, using morpholine instead of piperidine. Thus,2-[3-(morpholin-4-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 55”) was obtained.

Active Compound 55

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 8.13-8.11 (m,1H), 7.97 (d, J=4.9 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.7,1.7 Hz, 1H), 3.96-3.93 (m, 4H), 3.21-3.18 (m, 4H)

Production Example 57

A mixture of 0.31 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g ofimidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirredwhile heating at room temperature for 1.5 hours, and then at 60° C. for1.5 hours. The reaction mixture was cooled to room temperature, and thenwater was added to the reaction mixture, followed by extraction withethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.31 g of2-[3-(imidazole-1-yepyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 56”).

Active Compound 56

¹H-NMR (CDCl₃) δ: 8.93 (d, J=5.1 Hz, 1H), 8.82 (s, 1H), 8.23 (d, J=5.1Hz, 1H), 8.08-8.06 (m, 1H), 7.72-7.71 (m, 1H), 7.69 (dd, J=8.5, 1.3 Hz,1H), 7.59 (d, J=8.5 Hz, 1H), 7.29-7.28 (m, 1H), 7.13-7.11 (m, 1H)

Production Example 58

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of4-(trifluoromethyl)-1H-imidazole, 0.55 g of potassium carbonate and 2 mlof DMF was stirred while heating at 50° C. for 1.5 hours. Then, thereaction mixture was cooled to room temperature. Water was added to thereaction mixture, followed by extraction with ethyl acetate twice. Thecombined organic layers were washed with a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.40 g of2-{3-[4-(trifluoromethyl)imidazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 57”).

Active Compound 57

¹H-NMR (CDCl₃) δ: 9.00 (d, J=5.2 Hz, 1H), 8.84 (s, 1H), 8.31 (d, J=5.1Hz, 1H), 8.06-8.04 (m, 1H), 7.77-7.75 (m, 1H), 7.74-7.70 (m, 1H), 7.62(d, J=8.6 Hz, 1H), 7.52-7.50 (m, 1H)

Production Example 59

A mixture of 0.24 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g ofpyrazole, 0.69 g of potassium carbonate and 4 ml of DMF was stirredwhile heating at 50° C. for two hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.22 g of2-[3-(pyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 58”).

Active Compound 58

¹H-NMR (CDCl₃) δ: 8.93 (s, 1H), 8.87 (d, J=5.1 Hz, 1H), 8.10 (d, J=5.1Hz, 1H), 8.08-8.06 (m, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.7 Hz,1H), 7.66 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.55-6.53 (m,1H)

Production Example 60

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.19 g of3-bromopyrazole, 0.55 g of potassium carbonate and 2 ml of DMF wasstirred while heating at 50° C. for 1.5 hours. Then, the reactionmixture was cooled to room temperature. Water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.31 g of2-[3-(3-bromopyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 59”).

Active Compound 59

¹H-NMR (CDCl₃) δ: 8.92 (s, 1H), 8.89 (d, J=5.1 Hz, 1H), 8.16 (d, J=5.1Hz, 1H), 8.08-8.07 (m, 1H), 7.69 (dd, J=8.8, 1.2 Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H)

Production Example 61

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of3-trifluoromethylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMFwas stirred while heating at 60° C. for one hour. The reaction mixturewas cooled to room temperature, and then water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.34 g of2-[3-(3-trifluoromethylpyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 60”).

Active Compound 60

¹H-NMR (CDCl₃) δ: 8.95 (d, J=5.2 Hz, 1H), 8.94 (s, 1H), 8.22 (dd, J=5.2,0.7 Hz, 1H), 8.05-8.03 (m, 1H), 7.84-7.82 (m, 1H), 7.68 (dd, J=8.8, 1.3Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H)

Production Example 62

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of4-methylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMF wasstirred while heating at 60° C. for 1.5 hours. To the mixture, 0.05 g of4-methylpyrazole was added and further stirred while heating at 60° C.for 1.5 hours. Then, the reaction mixture was cooled to roomtemperature. Water was added to the reaction mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 0.25 gof2-[3-(4-methylpyrazole-1-yppyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 61”).

Active Compound 61

¹H-NMR (CDCl₃) δ: 8.89 (d, J=0.5 Hz, 1H), 8.81 (d, J=5.1 Hz, 1H),8.08-8.07 (m, 1H), 8.04 (dd, J=5.1, 0.6 Hz, 1H), 7.67-7.65 (m, 1H),7.57-7.54 (m, 2H), 7.51 (s, 1H), 2.19 (s, 3H)

Production Example 63

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of4-(trifluoromethyl)pyrazole, 0.55 g of potassium carbonate and 2 ml ofDMF was stirred while heating at 50° C. for 1.5 hours. The reactionmixture was cooled to room temperature. Water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.36 g of2-{3-[4-(trifluoromethyl)pyrazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 62”).

Active Compound 62

¹H-NMR (CDCl₃) δ: 8.96 (d, J=5.1 Hz, 1H), 8.93 (d, J=0.5 Hz, 1H), 8.21(dd, J=5.1, 0.5 Hz, 1H), 8.13-8.11 (m, 1H), 8.05-8.04 (m, 1H), 7.95 (s,1H), 7.71-7.68 (m, 1H), 7.56 (d, J=8.8 Hz, 1H)

Production Example 64

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of1H-1,2,4-triazole, 0.55 g of potassium carbonate and 2 ml of DMF wasstirred while heating at 50° C. for 1.5 hours. Then, the reactionmixture was cooled to room temperature. Water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.26 g of2-[3-(1,2,4-triazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 63”).

Active Compound 63

¹H-NMR (CDCl₃) δ: 8.99 (d, J=5.3 Hz, 1H), 8.92 (d, J=0.8 Hz, 1H), 8.52(s, 1H), 8.25 (dd, J=5.3, 0.6 Hz, 1H), 8.19 (s, 1H), 8.05-8.04 (m, 1H),7.71-7.69 (m, 1H), 7.61-7.59 (m, 1H)

Production Example 65

To a mixture of 0.42 g ofN-[3-chloro-5-(trifluoromethyl)-2-hydroxyphenyl]isonicotinamide, 5 ml oftetrahydrofuran and 0.38 g of triphenylphosphine, 0.64 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred while heating at roomtemperature for one hour and then at 50° C. for 2.5 hours. The reactionmixture was cooled to room temperature, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give2-(pyridin-4-yl)-7-chloro-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 64”).

Active Compound 64

¹H-NMR (CDCl₃) δ: 8.89-8.88 (m, 2H), 8.16-8.13 (m, 2H), 8.02-8.01 (m,1H), 7.72-7.71 (m, 1H)

Production Example 66

To a mixture of 0.49 g ofN-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide, 5 ml oftetrahydrofuran and 0.46 g of triphenylphosphine, 0.77 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 1.8 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.41 g of5-(pentafluoroethyl)-2-(pyridin-4-yl)-benzoxazole (hereinafter, referredto as “active compound 65”).

Active Compound 65

¹H-NMR (CDCl₃) δ: 8.88-8.86 (m, 2H), 8.12-8.10 (m, 3H), 7.77 (d, J=8.8Hz, 1H), 7.70-7.67 (m, 1H)

Production Example 67

To a mixture of 0.24 g of3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide, 4 mlof tetrahydrofuran and 0.21 g of triphenylphosphine, 0.34 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 1.8 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.19 g of2-(3-chloropyridin-4-yl)-5-(pentafluoroethyl)benzoxazole (hereinafter,referred to as “active compound 66”).

Active Compound 66

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.18 (s, 1H),8.10 (d, J=5.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H)

Production Example 68

To a mixture of 0.79 g ofN-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 8 ml oftetrahydrofuran and 0.60 g of triphenylphosphine, 0.99 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 2.3 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give2-(pyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole (hereinafter,referred to as “active compound 67”).

Active Compound 67

¹H-NMR (CDCl₃) δ: 8.88-8.86 (m, 2H), 8.14 (s, 1H), 8.12-8.10 (m, 2H),7.78 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H)

Production Example 69

To a mixture of 0.90 g of3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 10ml of tetrahydrofuran and 0.68 g of triphenylphosphine, 1.13 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 1.2 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.58 g of2-(3-chloropyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole(hereinafter, referred to as “active compound 68”).

Active Compound 68

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.21 (s, 1H),8.09 (d, J=4.9 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H)

Production Example 70

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of ethanol was stirred while heating at 60°C. for two hours and then at 90° C. for 2.5 hours. The reaction mixturewas cooled to room temperature, and then concentrated under reducedpressure. Water was added to the reaction mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.18 g of2-(3-ethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 69”).

Active Compound 69

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.14-8.12 (m,1H), 8.00 (d, J=4.8 Hz, 1H), 7.75-7.67 (m, 2H), 4.39 (q, J=7.0 Hz, 2H),1.58 (t, J=7.0 Hz, 3H)

Production Example 71

To a mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml of2-propanol, 52 mg of 60% sodium hydride (in oil) was added whileice-cooling. The mixture was stirred for 1.5 hours and then heated toroom temperature and stirred for 1.5 hours. Water was added to thereaction mixture, followed by extraction with ethyl acetate twice. Thecombined organic layers were washed with a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.12 g of2-(3-isopropoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 70”).

Active Compound 70

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.13-8.12 (m,1H), 8.00 (d, J=5.1 Hz, 1H), 7.74-7.67 (m, 2H), 4.87-4.78 (m, 1H), 1.49(d, J=6.0 Hz, 6H)

Production Example 72

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate, and 3 ml of propanol was heated to reflux whilestirring for six hours. The reaction mixture was cooled to roomtemperature, and then concentrated under reduced pressure. Water wasadded the reaction mixture, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.25 g of2-(3-propoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 71”).

Active Compound 71

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.13-8.11 (m,1H), 8.01 (d, J=5.1 Hz, 1H), 7.74-7.67 (m, 2H), 4.27 (t, J=6.5, 2H),2.02-1.92 (m, 2H), 1.15 (t, J=7.5 Hz, 3H)

Production Example 73

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of butanol was stirred while heating at100° C. for six hours. To the mixture, 0.14 g of potassium carbonate wasadded, and the reaction mixture was stirred while heating at 100° C. forfurther four hours. The reaction mixture was cooled to room temperature,and then water was added to the reaction mixture, followed by extractionwith ethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.24 g of2-(3-butoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 72”).

Active Compound 72

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.42 (d, J=4.8 Hz, 1H), 8.13-8.11 (m,1H), 8.01 (d, J=4.8 Hz, 1H), 7.73-7.67 (m, 2H), 4.31 (t, J=6.5 Hz, 2H),1.97-1.88 (m, 2H), 1.67-1.55 (m, 2H), 1.03 (t, J=7.5 Hz, 3H)

Production Example 74

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of 2-propyne-1-ol was stirred while heatingat 100° C. for two hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.20 g of2-(3-(2-propyne-1-yloxy)pyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 73”).

Active Compound 73

¹H-NMR (CDCl₃) δ: 8.75 (s, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.16-8.14 (m,1H), 8.05 (d, J=5.1 Hz, 1H), 7.77-7.69 (m, 2H), 5.05-5.03 (m, 2H),2.64-2.62 (m, 1H)

Production Example 75

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of allyl alcohol was stirred while heatingat 100° C. for two hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.24 g of2-(3-allyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 74”).

Active Compound 74

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.15-8.13 (m,1H), 8.03 (d, J=4.9 Hz, 1H), 7.75-7.68 (m, 2H), 6.19-6.09 (m, 1H),5.70-5.62 (m, 1H), 5.44-5.38 (m, 1H), 4.92-4.86 (m, 2H)

Production Example 76

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of 2,2,3,3,3-pentafluoropropanol was heatedto reflux while stirring for 5.5 hours. The reaction mixture was cooledto room temperature, and then water was added to the reaction mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give0.33 g of2-[3-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 75”).

Active Compound 75

¹H-NMR (CDCl₃) δ: 8.61-8.58 (m, 2H), 8.14-8.11 (m, 2H), 7.73-7.72 (m,2H), 4.77-4.70 (m, 2H)

Production Example 77

To a mixture of 0.69 g ofN-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, 9 ml oftetrahydrofuran, and 0.63 g of triphenylphosphine, 1.05 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature and stirred for three hours. To the mixture, 0.21 g oftriphenylphosphine and 0.35 g of 40% toluene solution of diethylazodicarboxylate were added. The reaction mixture was stirred forfurther two hours. The reaction mixture was concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyand the resultant crystals were washed with methanol to give 0.17 g of2-(pyridin-4-yl)-5-(trifluoromethylthio)benzoxazole (hereinafter,referred to as “active compound 76”).

Active Compound 76

¹H-NMR (CDCl₃) δ: 8.86 (dd, J=4.3, 1.7 Hz, 2H), 8.17-8.16 (m, 1H), 8.10(dd, J=4.3, 1.7 Hz, 2H), 7.74 (dd, J=8.7, 1.4 Hz, 1H), 7.69 (d, J=8.5Hz, 1H)

Production Example 78

To a mixture of 0.64 g of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, 6ml of tetrahydrofuran and 0.53 g of triphenylphosphine, 0.87 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature and stirred for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.57 g of2-(3-chloropyridin-4-yl)-5-(trifluoromethylthio)benzoxazole(hereinafter, referred to as “active compound 77”).

Active Compound 77

¹H-NMR (CDCl₃) δ: 8.85 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.7Hz, 1H), 8.09 (d, J=5.1 Hz, 1H), 7.78 (dd, J=8.5, 1.7 Hz, 1H), 7.72 (d,J=8.5 Hz, 1H)

Production Example 79

To a mixture of 0.55 g ofN-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide, 6 ml oftetrahydrofuran and 0.50 g of triphenylphosphine, 0.83 g of 40% toluenesolution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 1.5 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography, and the resultantcrystals were washed with methanol to give 0.11 g of5-chloro-2-(pyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 78”).

Active Compound 78

¹H-NMR (CDCl₃) δ: 8.88 (dd, J=4.3, 1.7 Hz, 2H), 8.10 (dd, J=4.5, 1.7 Hz,2H), 8.01 (s, 1H), 7.97 (s, 1H)

Production Example 80

To a mixture of 0.67 g of3-chloro-N-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide,7 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.91 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for 1.5 hours. To themixture, 0.14 g of triphenylphosphine and 0.23 g of 40% toluene solutionof diethyl azodicarboxylate were added and stirred for further one hour.The reaction mixture was concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and theresultant crystals were washed with isopropanol and hexane to give 0.37g of 5-chloro-2-(3-chloropyridin-4-yl)-6-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 79”).

Active Compound 79

¹H-NMR (CDCl₃) δ: 8.87 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.09 (d, J=5.1Hz, 1H), 8.06 (s, 1H), 8.03 (s, 1H)

Production Example 81

To a mixture of 1.01 g ofN-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 10 mlof tetrahydrofuran and 0.92 g of triphenylphosphine, 1.53 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature, and the reaction mixture was stirred for two hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography and the resultantcrystals washed with methanol to give 0.66 g of6-chloro-2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 80”).

Active Compound 80

¹H-NMR (CDCl₃) δ: 8.87 (dd, J=4.3, 1.7 Hz, 2H), 8.18 (s, 1H), 8.08 (dd,J=4.3, 1.7 Hz, 2H), 7.81 (s, 1H)

Production Example 82

To a mixture of 0.46 g of3-chloro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide,5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.63 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature, and the reaction mixture was stirred for two hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.39 g of6-chloro-2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 81”).

Active Compound 81

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.26 (s, 1H),8.08 (d, J=5.1 Hz, 1H), 7.86 (s, 1H)

Production Example 83

A mixture of 0.28 g of2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml ofacetic anhydride was stirred while heating at 60° C. for two hours. Thereaction mixture was cooled to room temperature, and then water wasadded to the reaction mixture, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was washed with ethyl acetate to give 0.17g of N-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]acetamide(hereinafter, referred to as “active compound 82”).

Active Compound 82

¹H-NMR (DMSO-d₆) δ: 10.92 (br s, 1H), 9.52 (s, 1H), 8.57 (d, J=5.1 Hz,1H), 8.44-8.42 (m, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.09-8.07 (m, 1H),7.93-7.90 (m, 1H), 2.26 (s, 3H)

Production Example 84

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.55 g ofpotassium carbonate, 0.14 g of methylamine hydrochloride, and 3 ml ofDMF was stirred while heating at 60° C. for three hours. To the mixture,0.55 g of potassium carbonate and 0.14 g of methylamine hydrochloridewere added, and the reaction mixture was stirred while heating forfurther two hours. Water was added to the reaction mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography, and resultantcrystals were washed with diethyl ether to give 0.13 g ofmethyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine(hereinafter, referred to as “active compound 83”).

Active Compound 83

¹H-NMR (CDCl₃) δ: 8.35 (s, 1H), 8.08-8.04 (m, 2H), 7.94-7.87 (br m, 1H),7.84 (d, J=5.1 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.69-7.65 (m, 1H), 3.16(d, J=5.1 Hz, 3H)

Production Example 85

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.55 g ofpotassium carbonate, 0.16 g of ethylamine hydrochloride and 3 ml of DMFwas stirred while heating at 80° C. for 4.5 hours. To the mixture, 0.55g of potassium carbonate, 0.16 g of ethylamine hydrochloride and 2 ml ofDMF were added, and the reaction mixture was stirred while heating forfurther three hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.19 g ofethyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]iamine(hereinafter, referred to as “active compound 84”).

Active Compound 84

¹H-NMR (CDCl₃) δ: 8.35 (s, 1H), 8.08-8.06 (m, 1H), 8.04 (d, J=5.1 Hz,1H), 7.92-7.87 (br m, 1H), 7.85 (d, J=5.1 Hz, 1H), 7.71 (d, J=8.7 Hz,1H), 7.69-7.65 (m, 1H), 3.54-3.45 (m, 2H), 1.46 (t, J=7.1 Hz, 3H)

Production Example 86

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.69 g ofpotassium carbonate, 0.30 g of isopropylamine and 3 ml of DMF wasstirred while heating at 50° C. for 1.5 hours and at 80° C. for 4 hours.To the mixture, 0.30 g of isopropylamine was added and stirred whileheating for further three hours. To the reaction mixture, water wasadded, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.21 g ofisopropyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine(hereinafter, referred to as “active compound 85”).

Active Compound 85

¹H-NMR (CDCl₃) δ: 8.36 (s, 1H), 8.09-8.07 (m, 1H), 8.00 (d, J=5.1 Hz,1H), 7.95-7.89 (br m, 1H), 7.85 (d, J=5.1 Hz, 1H), 7.70 (d, J=8.5 Hz,1H), 7.69-7.65 (m, 1H), 4.03-3.94 (m, 1H), 1.42 (d, J=6.3 Hz, 6H)

Production Example 87

To a mixture of 0.68 g of3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide,8 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.90 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature, and the reaction mixture was stirred for 1.5 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.55 g of2-(3-chloropyridin-4-yl)-5,5,7,7-tetrafluoro-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 86”).

Active Compound 86

¹H-NMR (CDCl₃) δ: 8.89 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.16 (s, 1H),8.11 (d, J=5.1 Hz, 1H), 7.96 (s, 1H)

Production Example 88

To a mixture of 1.46 g of3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide,10 ml of tetrahydrofuran and 2.02 g of triphenylphosphine, 0.90 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature, and the reaction mixture was stirred for one hour. Thereaction mixture was concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 1.09 g of5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 87”).

Active Compound 87

¹H-NMR (CDCl₃) δ: 8.80-8.78 (m, 1H), 8.71-8.68 (m, 1H), 8.17-8.12 (m,2H), 7.96-7.94 (m, 1H)

Production Example 89

A mixture of 0.28 g of5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole,0.24 g of potassium carbonate and 3 ml of methanol was stirred whileheating at 60° C. for 3.5 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.13 g of5,5,7,7-tetrafluoro-2-(3-methoxypyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 88”).

Active Compound 88

¹H-NMR (CDCl₃) δ: 8.63 (s, 1H), 8.49 (d, J=4.9 Hz, 1H), 8.10 (s, 1H),8.03 (d, J=4.9 Hz, 1H), 7.91 (s, 1H), 4.17 (s, 3H)

Production Example 90

A mixture of 44 mg of 60% sodium hydride (in oil) and 2 ml of DMF wasstirred at room temperature. To the mixture, a mixture solution of 0.11g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixturesolution was stirred for 15 minutes, and then, 0.28 g of5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazolewas added and stirred at room temperature for one hour. Water was addedto the reaction mixture, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.25 g of5,5,7,7-tetrafluoro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 89”).

Active Compound 89

¹H-NMR (CDCl₃) δ: 8.63-8.61 (m, 2H), 8.12 (d, J=4.9 Hz, 1H), 8.11 (s,1H), 7.91 (s, 1H), 4.69 (q, J=7.8 Hz, 2H)

Production Example 91

To a mixture of 2.08 g of3-fluoro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide,13 ml of tetrahydrofuran and 1.79 g of triphenylphosphine, 2.98 g of 40%toluene solution of diethyl azodicarboxylate was added dropwise at roomtemperature. The reaction mixture was stirred for one hour. The reactionmixture was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 1.74 g of6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 90”).

Active Compound 90

¹H-NMR (CDCl₃) δ: 8.77-8.75 (m, 1H), 8.68-8.65 (m, 1H), 8.24 (s, 1H),8.13-8.08 (m, 1H), 7.85 (s, 1H)

Production Example 92

A mixture of 0.28 g of6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.24 gof potassium carbonate and 3 ml of methanol was stirred while heating at60° C. for two hours. Water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.13 g of6-chloro-2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 91”).

Active Compound 91

¹H-NMR (CDCl₃) δ: 8.60 (s, 1H), 8.47 (d, J=4.9 Hz, 1H), 8.21 (s, 1H),7.99 (d, J=4.9 Hz, 1H), 7.81 (s, 1H), 4.16 (s, 3H)

Production Example 93

A mixture of 46 mg of 60% sodium hydride (in oil) and 2 ml of DMF wasstirred at room temperature, to which a mixture solution of 0.12 g of2,2,2-trifluoroethanol and 0.5 ml of DMF was added. After 15 minutes,0.28 g of6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole wasadded and stirred at room temperature for one hour. Water was added tothe reaction mixture, followed by extraction with ethyl acetate twice.The combined organic layers were washed with a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 0.26 g of6-chloro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 92”).

Active Compound 92

¹H-NMR (CDCl₃) δ: 8.60 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 8.21 (s, 1H),8.08 (d, J=5.1 Hz, 1H), 7.81 (s, 1H), 4.66 (q, J=8.0 Hz, 2H)

Production Example 94

Production Example 94 was carried out according to the same manner as inProduction Example 78, usingN-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]-3-ethyl isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.17 g of6-chloro-2-(3-ethylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 93”) was obtained.

Active Compound 93

¹H-NMR (CDCl₃) δ: 8.72 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.21 (s, 1H),7.98 (d, J=5.1 Hz, 1H), 7.81 (s, 1H), 3.27 (q, J=7.5 Hz, 2H), 1.34 (t,J=7.4 Hz, 3H)

Production Example 95

Production Example 95 was carried out according to the same manner as inProduction Example 22, using3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.63 g of2-(3-chloropyridin-4-yl)-6-fluoro-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 94”) was obtained.

Active Compound 94

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.17 (d, J=6.3Hz, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H)

Production Example 96

Production Example 96 was carried out according to the same manner as inProduction Example 78, using3-chloro-N-[2-fluoro-6-hydroxy-3-(trifluoromethyl)phenyl]isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 56 mg of2-(3-chloropyridin-4-yl)-4-fluoro-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 95”) was obtained.

Active Compound 95

¹H-NMR (CDCl₃) δ: 8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.12 (d, J=5.1Hz, 1H), 7.73 (dd, J=8.5, 6.3 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H)

Production Example 97

Production Example 97 was carried out according to the same manner as inProduction Example 78, usingN-[2-chloro-6-hydroxy-3-(trifluoromethyl)phenyl]isonicotinamide insteadof 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide,and thus 91 mg of4-chloro-2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 96”) was obtained.

Active Compound 96

¹H-NMR (CDCl₃) δ: 8.88 (dd, J=4.4, 1.7 Hz, 2H), 8.15 (dd, J=4.5, 1.6 Hz,2H), 7.80 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H)

Production Example 98

Production Example 98 was carried out according to the same manner as inProduction Example 22, using3-isopropoxy-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.12 g of5,5,7,7-tetrafluoro-2-(3-isopropoxypyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 97”) was obtained.

Active Compound 97

¹H-NMR (CDCl₃) δ: 8.59 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.08 (s, 1H),8.01 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 4.92-4.82 (m, 1H), 1.50 (d, J=6.1Hz, 6H)

Production Example 99

Production Example 99 was carried out according to the same manner as inProduction Example 78, using3-ethyl-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide andthus 0.40 g of2-(3-ethylpyridin-4-yl)-5,5,7,7-tetrafluoro-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole(hereinafter, referred to as “active compound 98”) was obtained.

Active Compound 98

¹H-NMR (CDCl₃) δ: 8.75 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.11 (s, 1H),8.02 (d, J=5.1 Hz, 1H), 7.91 (s, 1H), 3.29 (q, J=7.5 Hz, 2H), 1.35 (t,J=7.5 Hz, 3H)

Production Example 100

Production Example 100 was carried out according to the same manner asin Production Example 78, usingN-(5-tert-butyl-2-hydroxyphenyl)-3-fluoro isonicotinamide instead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 3.1 g of 5-tert-butyl-2-(3-fluoropyridin-4-yl)benzoxazole(hereinafter, referred to as “active compound 99”) was obtained.

Active Compound 99

¹H-NMR (CDCl₃) δ: 8.72-8.70 (m, 1H), 8.62-8.59 (m, 1H), 8.12-8.09 (m,1H), 7.91-7.89 (m, 1H), 7.59-7.51 (m, 2H), 1.41 (s, 9H)

Production Example 101

Production Example 101 was carried out according to the same manner asin Production Example 38, using5-tert-butyl-2-(3-fluoropyridin-4-yObenzoxazole instead of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, and thus 0.27 gof 5-tert-butyl-2-(3-methoxypyridin-4-yl)benzoxazole (hereinafter,referred to as “active compound 100”) was obtained.

Active Compound 100

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.43 (d, J=4.9 Hz, 1H), 8.00 (d, J=4.9Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.48 (dd,J=8.8, 2.0 Hz, 1H), 4.15 (s, 3H), 1.40 (s, 9H)

Production Example 102

Production Example 102 was carried out according to the same manner asin Production Example 40, using5-tert-butyl-2-(3-fluoropyridin-4-yl)benzoxazole instead of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole to give 0.33 gof 5-tert-butyl-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]benzoxazole(hereinafter, referred to as “active compound 101”) was obtained.

Active Compound 101

¹H-NMR (CDCl₃) δ: 8.59 (s, 1H), 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=4.9Hz, 1H), 7.86 (d, J=1.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.51 (dd,J=8.7, 1.8 Hz, 1H), 4.65 (q, J=8.0 Hz, 2H), 1.41 (s, 9H)

Production Example 103

A mixture of 2.07 g of 5-tert-butyl-2-(3-fluoropyridin-4-yl)benzoxazole,4.23 g of potassium carbonate and 8 ml of benzyl alcohol was stirredwhile heating at 100° C. for 8.5 hours. The reaction mixture was cooledto room temperature, and then water was added to the reaction mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give2.2 g of 2-(3-benzyloxypyridin-4-yl)-5-tert-butylbenzoxazole(hereinafter, referred to as “active compound 102”).

Active Compound 102

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.41 (d, J=4.9 Hz, 1H), 8.03 (d, J=4.9Hz, 1H), 7.88-7.86 (m, 1H), 7.59-7.55 (m, 2H), 7.54-7.47 (m, 2H),7.43-7.37 (m, 2H), 7.36-7.30 (m, 1H), 5.42 (s, 2H), 1.41 (s, 9H)

Production Example 104

A mixture of 2.1 g of2-(3-benzyloxypyridin-4-yl)-5-tert-butylbenzoxazole, 0.58 g of 5%palladium on carbon and 50 ml of acetic acid was stirred under about oneatmosphere of hydrogen at room temperature for six hours. The reactionmixture was filtered through Celite™. The filtrate was concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 1.3 g of4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol (hereinafter, referred toas “active compound 103”).

Active Compound 103

¹H-NMR (CDCl₃) δ: 11.21 (br s, 1H), 8.60 (s, 1H), 8.31 (d, J=4.9 Hz,1H), 7.83-7.80 (m, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.7, 1.8 Hz,1H), 1.42 (s, 9H)

Production Example 105

To a mixture of 0.30 g of 4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol,0.17 g of potassium carbonate and 3 ml of DMF, 0.21 g of isopropyliodide was added at room temperature. The reaction mixture was stirredwhile heating at 60° C. for two hours. The mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.21 g of5-tert-butyl-2-(3-isopropoxypyridin-4-yl)benzoxazole (hereinafter,referred to as “active compound 104”).

Active Compound 104

¹H-NMR (CDCl₃) δ: 8.53 (s, 1H), 8.38 (d, J=4.9 Hz, 1H), 7.98 (d, J=5.0Hz, 1H), 7.86-7.84 (m, 1H), 7.55-7.46 (m, 2H), 4.81-4.70 (m, 1H), 1.47(d, J=6.1 Hz, 6H), 1.41 (s, 9H)

Production Example 106

Production Example 106 was carried out according to the same manner asin Production Example 78, using N-(5-tert-butyl-2-hydroxyphenyl)-3-ethylisonicotinamide instead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.19 g of 5-tert-butyl-2-(3-ethylpyridin-4-yl)benzoxazole(hereinafter, referred to as “active compound 105”) was obtained.

Active Compound 105

¹H-NMR (CDCl₃) δ: 8.67 (s, 1H), 8.61 (d, J=5.1 Hz, 1H), 7.99 (d, J=5.1Hz, 1H), 7.87-7.85 (m, 1H), 7.56-7.47 (m, 2H), 3.29 (q, J=7.5 Hz, 2H),1.41 (s, 9H), 1.34 (t, J=7.5 Hz, 3H)

Production Example 107

Production Example 106 was carried out according to the same manner asin Production Example 78, usingN-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.59 g of5-tert-butyl-2-[2-chloro-5-(trifluoromethyl)pyridin-4-yl]benzoxazole(hereinafter, referred to as “active compound 106”) was obtained.

Active Compound 106

¹H-NMR (CDCl₃) δ: 8.89 (s, 1H), 8.23 (s, 1H), 7.90-7.88 (m, 1H),7.58-7.57 (m, 2H), 1.41 (s, 9H)

Production Example 108

A mixture of 0.40 g of5-tert-butyl-2-(2-chloro-5-trifluoromethylpyridin-4-yl)benzoxazole, 0.59g of 5% palladium on carbon and 25 ml of acetic acid was stirred underabout one atmosphere of hydrogen at room temperature for 15 hours. Thereaction mixture was filtered through Celite™. The filtrate wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.19 g of5-tert-butyl-2-(3-trifluoromethylpyridin-4-yObenzoxazole (hereinafter,referred to as “active compound 107”).

Active Compound 107

¹H-NMR (CDCl₃) δ: 9.13 (s, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.14 (d, J=5.1Hz, 1H), 7.89 (dd, J=1.7, 0.7 Hz, 1H), 7.58 (d, J=8.6, 0.7 Hz, 1H), 7.54(dd, J=8.8, 1.8 Hz, 1H), 1.41 (s, 9H)

Production Example 109

Production Example 109 was carried out according to the same manner asin Production Example 78, using3-chloro-N-(2-hydroxy-5-trifluoromethoxyphenyl)isonicotinamide ofinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.32 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethoxy)benzoxazole(hereinafter, referred to as “active compound 108”) was obtained.

Active Compound 108

¹H-NMR (CDCl₃) δ: 8.85-8.84 (m, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.09-8.07(m, 1H), 7.79-7.77 (m, 1H), 7.69-7.66 (m, 1H), 7.38-7.34 (m, 1H)

Production Example 110

Production Example 110 was carried out according to the same manner asin Production Example 22, using3-ethyl-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide insteadof 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.32 g of 2-(3-ethylpyridin-4-yl)-5-(trifluoromethoxy)benzoxazole(hereinafter, referred to as “active compound 109”) was obtained.

Active Compound 109

¹H-NMR (CDCl₃) δ: 8.70 (s, 1H), 8.65 (d, J=5.1 Hz, 1H), 7.99 (d, J=5.1Hz, 1H), 7.74-7.72 (m, 1H), 7.65-7.62 (m, 1H), 7.34-7.30 (m, 1H), 3.28(q, J=7.5 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H)

Production Example 111

Production Example 111 was carried out according to the same manner asin Production Example 40, using 2,2-difluoroethanol instead of2,2,2-trifluoroethanol, and thus 0.24 g of2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 110”) was obtained.

Active Compound 110

¹H-NMR (CDCl₃) δ: 8.59 (s, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.14 (s, 1H),8.07 (d, J=4.9 Hz, 1H), 7.76-7.70 (m, 2H), 6.28 (tt, J=54.9, 4.0 Hz,1H), 4.51 (td, J=12.8, 4.0 Hz, 2H)

Production Example 112

Production Example 112 was carried out according to the same manner asin Production Example 40, using 1,1,1-trifluoro-2-propanol instead of2,2,2-trifluoroethanol, and thus 0.31 g of2-[3-(1-methyl-2,2,2-trifluoroethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 111”) was obtained.

Active Compound 111

¹H-NMR (CDCl₃) δ: 8.61 (s, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.14-8.12 (m,1H), 8.09 (d, J=4.9 Hz, 1H), 7.76-7.70 (m, 2H), 4.97-4.87 (m, 1H), 1.69(d, J=6.6 Hz, 3H)

Production Example 113

Production Example 113 was carried out according to the same manner asin Production Example 40, using 2,2,3,3-tetrafluoropropanol instead of2,2,2-trifluoroethanol, and thus 0.34 g of2-[3-(2,2,3,3-tetrafluoropropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 112”) was obtained.

Active Compound 112

¹H-NMR (CDCl₃) δ: 8.58 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 8.13-8.12 (m,1H), 8.10 (d, J=4.9 Hz, 1H), 7.74-7.73 (m, 2H), 6.75-6.44 (m, 1H),4.71-4.63 (m, 2H)

Production Example 114

Production Example 114 was carried out according to the same manner asin Production Example 103, using2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole instead of5-tert-butyl-2-(3-fluoropyridin-4-yl)benzoxazole, and thus 4.6 g of2-(3-benzyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 113”) was obtained.

Active Compound 113

¹H-NMR (CDCl₃) δ: 8.62 (s, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.15-8.13 (m,1H), 8.05 (d, J=5.0 Hz, 1H), 7.73-7.67 (m, 2H), 7.60-7.54 (m, 2H),7.45-7.39 (m, 2H), 7.38-7.33 (m, 1H), 5.44 (s, 2H)

Production Example 115

A mixture of 4.69 g of2-(3-benzyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.0 g of 5%palladium on carbon and 70 ml of acetic acid was stirred under about oneatmosphere of hydrogen at room temperature for nine hours. The reactionmixture was filtered through Celite™. The filtrate was concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 3.44 g of4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol (hereinafter,referred to as “active compound 114”).

Active Compound 114

¹H-NMR (CDCl₃) δ: 10.84 (br s, 1H), 8.63 (s, 1H), 8.35 (d, J=4.9 Hz,1H), 8.12-8.09 (m, 1H), 7.86 (d, J=5.1 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H),7.76 (dd, J=8.5, 1.7 Hz, 1H)

Production Example 116

To a mixture of 0.28 g of4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 0.28 g of potassiumcarbonate and 2 ml of DMF, a mixture of 0.29 g of cyclopentyl bromideand 2 ml of DMF was added at room temperature. The reaction mixture wasstirred while heating at 60° C. for four hours. The reaction mixture wascooled to room temperature, and then water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.29 g of2-(3-cyclopentyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 115”).

Active Compound 115

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.39 (d, J=4.9 Hz, 1H), 8.13-8.10 (m,1H), 8.00 (d, J=4.9 Hz, 1H), 7.73-7.66 (m, 2H), 5.13-5.06 (m, 1H),2.08-1.99 (m, 4H), 1.96-1.84 (m, 2H), 1.77-1.65 (m, 2H)

Production Example 117

Production Example 117 was carried out according to the same manner asin Production Example 72, using isobutyl alcohol instead of propanol,and thus 0.24 g of2-(3-isobutoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 116”) was obtained.

Active Compound 116

¹H-NMR (CDCl₃) δ: 8.55 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12-8.11 (m,1H), 8.02 (d, J=5.1 Hz, 1H), 7.73-7.67 (m, 2H), 4.06 (d, J=6.3 Hz, 2H),2.32-2.20 (m, 1H), 1.14 (d, J=6.6 Hz, 6H)

Production Example 118

Production Example 118 was carried out according to the same manner asin Production Example 72, using 2,2-dimethyl-1-propanol instead ofpropanol, and thus 0.23 g of2-[3-(2,2-dimethylpropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 117”) was obtained.

Active Compound 117

¹H-NMR (CDCl₃) δ: 8.53 (s, 1H), 8.42 (d, J=4.9 Hz, 1H), 8.12-8.10 (m,1H), 8.04 (d, J=4.9 Hz, 1H), 7.72-7.66 (m, 2H), 3.93 (s, 2H), 1.15 (s,9H)

Production Example 119

Production Example 119 was carried out according to the same manner asin Production Example 72, using cyclopropane methanol instead ofpropanol, and thus 0.23 g of2-[3-(cyclopropylmethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 118”) was obtained.

Active Compound 118

¹H-NMR (CDCl₃) δ: 8.57 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.14-8.12 (m,1H), 8.01 (d, J=5.0 Hz, 1H), 7.75-7.68 (m, 2H), 4.19 (d, J=6.5 Hz, 2H),1.45-1.34 (m, 1H), 0.73-0.65 (m, 2H), 0.51-0.45 (m, 2H)

Production Example 120

Production Example 120 was carried out according to the same manner asin Production Example 116, using 2-bromobutane instead of cyclopentylbromide, and thus 0.14 g of2-(3-sec-butoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 119”) was obtained.

Active Compound 119

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.39 (d, J=5.1 Hz, 1H), 8.13-8.11 (m,1H), 8.00 (d, J=5.1 Hz, 1H), 7.73-7.66 (m, 2H), 4.68-4.58 (m, 1H),1.96-1.73 (m, 2H), 1.45 (d, J=6.1 Hz, 3H), 1.07 (t, J=7.4 Hz, 3H)

Production Example 121

A mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g ofpotassium carbonate and 3 ml of 2-methoxyethanol was stirred whileheating at 80° C. for 2.5 hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.23 g of2-[3-(2-methoxyethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 120”).

Active Compound 120

¹H-NMR (CDCl₃) δ: 8.61 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 8.13-8.11 (m,1H), 8.02 (d, J=4.9 Hz, 1H), 7.73-7.67 (m, 2H), 4.48-4.42 (m, 2H),3.94-3.87 (m, 2H), 3.50 (s, 3H)

Production Example 122

Production Example 122 was carried out according to the same manner asin Production Example 121, using 3-methoxy-1-propanol instead of2-methoxyethanol, and thus 0.23 g of2-[3-(3-methoxypropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 121”) was obtained.

Active Compound 121

¹H-NMR (CDCl₃) δ: 8.59 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.13-8.10 (m,1H), 8.01 (d, J=4.9 Hz, 1H), 7.74-7.67 (m, 2H), 4.40 (t, J=6.2 Hz, 2H),3.69 (t, J=6.1 Hz, 2H), 3.37 (s, 3H), 2.23-2.17 (m, 2H)

Production Example 123

Production Example 123 was carried out according to the same manner asin Production Example 116, using 2-bromoethyl ethyl ether instead ofcyclopentyl bromide, and thus 0.10 g of 2-[3-(2-ethoxyethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter,referred to as “active compound 122”) was obtained.

Active Compound 122

¹H-NMR (CDCl₃) δ: 8.62 (s, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.12-8.10 (m,1H), 8.01 (d, J=4.9 Hz, 1H), 7.73-7.67 (m, 2H), 4.48-4.43 (m, 2H),3.96-3.91 (m, 2H), 3.66 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H)

Production Example 124

Production Example 124 was carried out according to the same manner asin Production Example 72, using pentanol instead of propanol, and thus0.29 g of 2-(3-pentyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 123”) was obtained.

Active Compound 123

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.42 (d, J=4.9 Hz, 1H), 8.13-8.10 (m,1H), 8.01 (d, J=4.9 Hz, 1H), 7.73-7.67 (m, 2H), 4.29 (t, J=6.5 Hz, 2H),1.99-1.90 (m, 2H), 1.62-1.52 (m, 2H), 1.49-1.37 (m, 2H), 0.96 (t, J=7.2Hz, 3H)

Production Example 125

Production Example 125 was carried out according to the same manner asin Production Example 72, using hexanol instead of propanol, and thus0.23 g of 2-(3-hexyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 124”) was obtained.

Active Compound 124

¹H-NMR (CDCl₃) δ: 8.56 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 8.15-8.09 (m,1H), 8.01 (d, J=5.1 Hz, 1H), 7.74-7.68 (m, 2H), 4.32-4.27 (m, 2H),1.98-1.88 (m, 2H), 1.61-1.52 (m, 2H), 1.42-1.31 (m, 4H), 0.95-0.88 (m,3H)

Production Example 126

Production Example 126 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, anthus 0.55 g of5-trifluoromethyl-2-[3-(trifluoromethyl)pyridin-4-yl]-benzoxazole(hereinafter, referred to as “active compound 125”) was obtained.

Active Compound 125

¹H-NMR (CDCl₃) δ: 9.18 (s, 1H), 9.04 (d, J=4.9 Hz, 1H), 8.20-8.18 (m,1H), 8.16 (d, J=5.1 Hz, 1H), 7.81-7.74 (m, 2H)

Production Example 127

A mixture of 0.50 g of4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 1.23 g of potassiumcarbonate and 14 ml of DMF was stirred while heating at 70° C. for threehours with chlorodifluoromethane gas injected. By stopping injection ofgas, the mixture was cooled to room temperature and allowed to standovernight. Water was added to the reaction mixture, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with water and a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give0.11 g of2-(3-difluoromethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 126”).

Active Compound 126

¹H-NMR (CDCl₃) δ: 8.80 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.18-8.16 (m,1H), 8.15 (d, J=5.1 Hz, 1H), 7.79-7.72 (m, 2H), 6.82 (t, J=73.0 Hz, 1H)

Production Example 128

Production Example 128 was carried out according to the same manner asin Production Example 39, using 3-hydroxy pyridine instead of phenol,and thus 0.30 g of2-[3-(pyridin-3-yloxy)-pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 127”) was obtained.

Active Compound 127

¹H-NMR (CDCl₃) δ: 8.67 (d, J=5.1 Hz, 1H), 8.54 (s, 1H), 8.53-8.52 (m,1H), 8.45-8.42 (m, 1H), 8.20-8.18 (m, 1H), 8.10-8.08 (m, 1H), 7.71-7.65(m, 2H), 7.40-7.36 (m, 1H), 7.35-7.30 (m, 1H),

Production Example 129

To a mixture of 0.40 g of2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g of3-pyridine boronic acid, 8 ml of 1,4-dioxane and 0.07 g ofdichlorobis(triphenylphosphine)palladium (II), a mixture of 0.40 g ofsodium carbonate and 3 ml of water was added and heated to reflux fortwo hours. The reaction mixture was cooled to room temperature, and thenwater was added to the reaction mixture, followed by extraction withethyl acetate. The combined organic layers were washed with water and asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.36 g of4-(5-trifluoromethyl-benzoxazole-2-yl)-[3,3′]bipyridinyl (hereinafter,referred to as “active compound 128”).

Active Compound 128

¹H-NMR (CDCl₃) δ: 8.89 (d, J=5.1 Hz, 1H), 8.77 (s, 1H), 8.74-8.69 (m,1H), 8.68-8.62 (m, 1H), 8.18-8.13 (m, 1H), 8.04-7.99 (m, 1H), 7.73-7.68(m, 1H), 7.67-7.62 (m, 1H), 7.54-7.47 (m, 1H), 7.43-7.36 (m, 1H)

Production Example 130

Production Example 130 was carried out according to the same manner asin Production Example 129, using 4-pyridine boronic acid instead of3-pyridine boronic acid, and thus 0.20 g of4-(5-trifluoromethyl-benzoxazole-2-yl)-[3,4′]bipyridinyl (hereinafter,referred to as “active compound 129”) was obtained.

Active Compound 129

¹H-NMR (CDCl₃) δ: 8.90 (d, J=5.1 Hz, 1H), 8.75 (s, 1H), 8.70 (dd, J=4.4,1.7 Hz, 2H), 8.14-8.12 (m, 1H), 8.03-8.02 (m, 1H), 7.67-7.63 (m, 1H),7.50 (d, J=8.5 Hz, 1H), 7.28 (dd, J=4.4, 1.7, 2H)

Production Example 131

A mixture of 0.30 g of2-(3-aminopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml oftrifluoroacetic anhydride was stirred while heating at 60° C. for 15minutes. The reaction mixture was cooled to room temperature, and thenwater and a saturated aqueous solution of sodium hydrogencarbonate wereadded to the reaction mixture. The precipitated crystals were filtered.The resultant crystals were dissolved in ethyl acetate. The resultantsolution was washed with a saturated sodium chloride solution, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.32 g of2,2,2-trifluoro-N-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]acetamide(hereinafter, referred to as “active compound 130”).

Active Compound 130

¹H-NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 10.11 (s, 1H), 8.71 (d, J=5.1 Hz,1H), 8.15-8.14 (m, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.85-7.79 (m, 2H)

Production Example 132

To a mixture of 0.28 g of2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g ofpotassium carbonate and 3 ml of DMF, 3 ml of a THF solution ofdimethylamine was added and stirred while heating at 60° C. for 3.3hours. The reaction mixture was cooled to room temperature, and thenwater was added to the reaction mixture, followed by extraction withethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography, and the resultantcrystals were washed with diethyl ether to give 0.27 g ofdimethyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine(hereinafter, referred to as “active compound 131”).

Active Compound 131

¹H-NMR (CDCl₃) δ: 8.53 (s, 1H), 8.28 (d, J=5.1 Hz, 1H), 8.13-8.11 (m,1H), 7.79 (d, J=5.1 Hz, 1H), 7.74-7.71 (m, 1H), 7.70-7.67 (m, 1H), 2.93(s, 6H)

Production Example 133

Production Example 133 was carried out according to the same manner asin Production Example 86, using N-isopropylmethylamine instead ofisopropylamine, and thus 0.17 g ofisopropyl-methyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine (hereinafter, referred to as “active compound 132”) was obtained.

Active Compound 132

¹H-NMR (CDCl₃) δ: 8.53 (s, 1H), 8.29 (d, J=4.9 Hz, 1H), 8.11-8.09 (m,1H), 7.79 (d, J=4.9 Hz, 1H), 7.73-7.66 (m, 2H), 3.57-3.45 (m, 1H), 2.82(s, 3H), 1.15 (d, J=6.6 Hz, 6H)

Production Example 134

To a mixture of 0.60 g of 2-(3-ethylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 8 ml of chloroform,0.64 g of 70% m-chloroperbenzoic acid was added while ice-cooling andstirred at 0° C. for one hour. The reaction mixture was diluted withchloroform, washed with 5% aqueous solution of sodium hydroxide and asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.21 g of2-[3-(ethanesulfonyl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 133”) and 0.30 g of2-[3-(ethanesulfinyl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 134”).

Active Compound 133

¹H-NMR (CDCl₃) δ: 9.44-9.43 (m, 1H), 9.09 (d, J=4.9 Hz, 1H), 8.17-8.14(m, 1H), 7.96-7.94 (m, 1H), 7.78-7.75 (m, 2H), 3.93 (q, J=7.5 Hz, 2H),1.46 (t, J=7.6 Hz, 3H)

Active Compound 134

¹H-NMR (CDCl₃) δ: 9.45-9.44 (m, 1H), 8.99 (d, J=5.1 Hz, 1H), 8.18-8.17(m, 1H), 8.13-8.11 (m, 1H), 7.81-7.76 (m, 2H), 3.53-3.41 (m, 1H),3.15-3.04 (m, 1H), 1.45 (t, J=7.4 Hz, 3H)

Production Example 135

Production Example 135 was carried out according to the same manner asin Production Example 134, using2-(3-methylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole instead of2-(3-ethylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, and thus0.26 g of2-[3-(methanesulfonyl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 135”) and 0.37 g of2-[3-(methanesulfinyl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 136”) were obtained.

Active Compound 135

¹H-NMR (CDCl₃) δ: 9.51 (s, 1H), 9.11 (d, J=4.9 Hz, 1H), 8.19-8.16 (m,1H), 7.97 (d, J=5.0 Hz, 1H), 7.80-7.76 (m, 2H), 3.72 (s, 3H)

Active Compound 136

¹H-NMR (CDCl₃) δ: 9.55 (s, 1H), 9.01 (d, J=5.1 Hz, 1H), 8.21-8.19 (m,1H), 8.12-8.10 (m, 1H), 7.82-7.76 (m, 2H), 3.13 (s, 3H)

Production Example 136

Production Example 136 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(methoxymethyl)isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.26 g of2-[3-(methoxymethyl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole(hereinafter, referred to as “active compound 137”) was obtained.

Active Compound 137

¹H-NMR (CDCl₃) δ: 9.02-9.01 (m, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.17-8.15(m, 1H), 8.08-8.05 (m, 1H), 7.77-7.71 (m, 2H), 5.12 (s, 2H), 3.57 (s,3H)

Production Example 137

Production Example 137 was carried out according to the same manner asin Production Example 22, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide instead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.32 g of 2-pyridin-4-yl-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 138”) was obtained.

Active Compound 138

¹H-NMR (CDCl₃) δ: 8.90 (dd, J=4.5, 1.6 Hz, 2H), 8.76-8.74 (m, 1H),8.40-8.38 (m, 1H), 8.14 (dd, J=4.4, 1.7 Hz, 2H)

Production Example 138

Production Example 138 was carried out according to the same manner asin Production Example 22, using3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.72 g of2-(3-chloropyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 139”) was obtained.

Active Compound 139

¹H-NMR (CDCl₃) δ: 8.89 (s, 1H), 8.80-8.77 (m, 1H), 8.74 (d, J=5.1 Hz,1H), 8.48-8.46 (m, 1H), 8.13 (d, J=5.1 Hz, 1H)

Production Example 139

To a mixture of 0.45 g of2-(3-chloropyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine and 5ml of chloroform, 0.48 g of 70% m-chloroperbenzoic acid was added inice-cooling and stirred while heating at room temperature for four hoursand at 50° C. for two hours. The reaction mixture was cooled to roomtemperature, then diluted with chloroform, and washed with 5% aqueoussolution of sodium hydroxide and a saturated sodium chloride solution,sequentially. The organic layer was dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.36 g of2-(3-chloro-1-oxypyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 140”).

Active Compound 140

¹H-NMR (CDCl₃) δ: 8.77-8.74 (m, 1H), 8.43-8.42 (m, 1H), 8.41 (d, J=1.7Hz, 1H), 8.23 (dd, J=7.0, 1.6 Hz, 1H), 8.19 (d, J=6.9 Hz, 1H)

Production Example 140

Production Example 140 was carried out according to the same manner asin Production Example 22, using3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 1.72 g of2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 141”) was obtained.

Active Compound 141

¹H-NMR (CDCl₃) δ: 8.81-8.76 (m, 2H), 8.70 (d, J=5.1 Hz, 1H), 8.46-8.43(m, 1H), 8.17-8.13 (m, 1H)

Production Example 141

Production Example 141 was carried out according to the same manner asin Production Example 22, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methylisonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.23 g of2-(3-methylpyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 142”) was obtained.

Active Compound 142

¹H-NMR (CDCl₃) δ: 8.76-8.74 (m, 1H), 8.72 (s, 1H), 8.70 (d, J=5.1 Hz,1H), 8.43-8.41 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 2.84 (s, 3H)

Production Example 142

Production Example 142 was carried out according to the same manner asin Production Example 22, using3-ethyl-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.16 g of2-(3-ethylpyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 143”) was obtained.

Active Compound 143

¹H-NMR (CDCl₃) δ: 8.76-8.73 (m, 2H), 8.70 (d, J=5.1 Hz, 1H), 8.43-8.41(m, 1H), 8.07 (d, J=5.1 Hz, 1H), 3.30 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5Hz, 3H)

Production Example 143

Production Example 143 was carried out according to the same manner asin Production Example 22, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-(trifluoromethyl)isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.22 g of6-trifluoromethyl-2-[3-(trifluoromethyl)pyridin-4-yl]-oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 144”) was obtained.

Active Compound 144

¹H-NMR (CDCl₃) δ: 9.21 (s, 1H), 9.08 (d, J=5.1 Hz, 1H), 8.81-8.79 (m,1H), 8.49-8.47 (m, 1H), 8.17 (d, J=5.1 Hz, 1H)

Production Example 144

Production Example 144 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methoxyisonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.27 g of2-(3-methoxypyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 145”) was obtained.

Active Compound 145

¹H-NMR (CDCl₃) δ: 8.75-8.72 (m, 1H), 8.63 (s, 1H), 8.49 (d, J=4.9 Hz,1H), 8.41-8.40 (m, 1H), 8.06-8.04 (m, 1H), 4.18 (s, 3H)

Production Example 145

Production Example 145 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methylthioisonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 1.07 g of2-(3-methylthiopyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 146”) was obtained.

Active Compound 146

¹H-NMR (CDCl₃) δ: 8.76-8.74 (m, 1H), 8.71 (s, 1H), 8.60 (d, J=5.1 Hz,1H), 8.48-8.46 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 2.70 (s, 3H)

Production Example 146

Production Example 146 was carried out according to the same manner asin Production Example 134, using2-(3-methylthiopyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridineinstead of 2-(3-ethylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole,and thus 0.20 g of2-[3-(methanesulfonyl)pyridin-4-yl]-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 147”) and 0.29 g of2-[3-(methanesulfinyl)pyridin-4-yl]-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 148”) were obtained.

Active Compound 147

¹H-NMR (CDCl₃) δ: 9.52 (d, J=0.5 Hz, 1H), 9.14 (t, J=5.1 Hz, 1H),8.81-8.79 (m, 1H), 8.47-8.46 (m, 1H), 8.00 (dd, J=5.0, 0.6 Hz, 1H), 3.69(s, 3H)

Active Compound 148

¹H-NMR (CDCl₃) δ: 9.59 (s, 1H), 9.07-9.05 (m, 1H), 8.82-8.80 (m, 1H),8.51-8.19 (m, 1H), 8.19-8.16 (m, 1H), 3.12 (s, 3H)

Production Example 147

Production Example 147 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-ethylthioisonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 1.06 g of2-(3-ethylthiopyridin-4-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 149”) was obtained.

Active Compound 149

¹H-NMR (CDCl₃) δ: 8.77-8.73 (m, 2H), 8.59 (d, J=5.1 Hz, 1H), 8.48-8.47(m, 1H), 8.08-8.06 (m, 1H), 3.21 (q, J=7.4 Hz, 2H), 1.49 (t, J=7.3 Hz,3H)

Production Example 148

Production Example 148 was carried out according to the same manner asin Production Example 134, using2-(3-ethylthiopyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridineinstead of 2-(3-ethylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole,and thus 0.29 g of2-[3-(ethanesulfonyl)pyridin-4-yl]-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 150”) and 0.20 g of2-[3-(ethanesulfinyl)pyridin-4-yl]-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 151”) were obtained.

Active Compound 150

¹H-NMR (CDCl₃) δ: 9.46-9.45 (m, 1H), 9.14 (d, J=4.9 Hz, 1H), 8.80-8.79(m, 1H), 8.46-8.44 (m, 1H), 7.99-7.97 (m, 1H), 3.88 (q, J=7.5 Hz, 2H),1.48 (t, J=7.3 Hz, 3H)

Active Compound 151

¹H-NMR (CDCl₃) δ: 9.48 (s, 1H), 9.04 (d, J=5.1 Hz, 1H), 8.82-8.80 (m,1H), 8.49-8.47 (m, 1H), 8.19-8.17 (m, 1H), 3.51-3.39 (m, 1H), 3.14-3.04(m, 1H), 1.44 (t, J=7.4 Hz, 3H)

Production Example 149

Production Example 149 was carried out according to the same manner asin Production Example 78, usingN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-(methoxymethyl)isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.29 g of2-[3-(methoxymethyl)pyridin-4-yl]-6-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 152”) was obtained.

Active Compound 152

¹H-NMR (CDCl₃) δ: 9.04 (s, 1H), 8.82 (d, J=5.1 Hz, 1H), 8.77-8.75 (m,1H), 8.44-8.42 (m, 1H), 8.12 (d, J=5.1 Hz, 1H), 5.11 (s, 2H), 3.56 (s,3H)

Production Example 150

Production Example 150 was carried out according to the same manner asin Production Example 22, usingN-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-isonicotinamide instead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 0.27 g of2-(pyridin-4-yl)-5-(trifluoromethyl)oxazolo[5,4-b]pyridine (hereinafter,referred to as “active compound 153”) was obtained.

Active Compound 153

¹H-NMR (CDCl₃) δ: 8.91 (dd, J=4.4, 1.7 Hz, 2H), 8.30 (d, J=8.0 Hz, 1H),8.14 (dd, J=4.4, 1.7 Hz, 2H), 7.85 (d, J=8.0 Hz, 1H)

Production Example 151

Production Example 151 was carried out according to the same manner asin Production Example 78, using3-chloro-N-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-isonicotinamideinstead of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, andthus 0.42 g of2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 154”) was obtained.

Active Compound 154

¹H-NMR (CDCl₃) δ: 8.89 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.38 (d, J=8.0Hz, 1H), 8.14-8.12 (m, 1H), 7.88 (d, J=8.0 Hz, 1H)

Production Example 152

Production Example 152 was carried out according to the same manner asin Production Example 139, using2-(3-chloropyridin-4-yl)-5-trifluoromethyl-oxazolo[5,4-b]pyridineinstead of2-(3-chloropyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine, andthus 0.14 g of2-(3-chloro-1-oxypyridin-4-yl)-5-(trifluoromethyl)oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 155”) was obtained.

Active Compound 155

¹H-NMR (CDCl₃) δ: 8.41 (d, J=1.7 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.23(dd, J=7.1, 1.7 Hz, 1H), 8.19 (d, J=7.1 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H)

Production Example 153

Production Example 153 was carried out according to the same manner asin Production Example 1, using 2-amino-6-methylpyridin-3-ol instead of2-amino-4-propylphenol, and thus 0.62 g of5-methyl-2-pyridin-4-yl-oxazolo[4,5-b]pyridine (hereinafter, referred toas “active compound 156”) was obtained.

Active Compound 156

¹H-NMR (CDCl₃) δ: 8.85 (dd, J=4.5, 1.6 Hz, 2H), 8.13 (dd, J=4.5, 1.6 Hz,2H), 7.82 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 2.72 (s, 3H)

Production Example 154

Production Example 154 was carried out according to the same manner asin Production Example 1, using 2-amino-6-methylpyridin-3-ol and3-chloroisonicotinic acid instead of 2-amino-4-propylphenol andisonicotinic acid, and thus 0.44 g of2-(3-chloropyridin-4-yl)-5-methyl-oxazolo[4,5-b]pyridine (hereinafter,referred to as “active compound 157”) was obtained.

Active Compound 157

¹H-NMR (CDCl₃) δ: 8.83 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.16 (d, J=5.1Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 2.74 (s, 3H)

Production Example 155

Production Example 154 was carried out according to the same manner asin Production Example 22, using3-benzyloxy-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-isonicotinamideinstead of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, andthus 2.23 g of2-[3-(benzyloxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 158”) was obtained.

Active Compound 158

¹H-NMR (CDCl₃) δ: 8.75-8.73 (m, 1H), 8.63 (s, 1H), 8.47 (d, J=4.9 Hz,1H), 8.40-8.38 (m, 1H), 8.06 (d, J=4.9 Hz, 1H), 7.60-7.56 (m, 2H),7.45-7.40 (m, 2H), 7.38-7.32 (m, 1H), 5.47 (s, 2H)

Production Example 156

A mixture of 1.7 g of2-[3-(benzyloxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine,40 ml of ethyl acetate and 10% palladium on carbon was reacted under theconditions of 40 bar and 40° C. for two hours. The reaction solution wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 1.0 g of4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol(hereinafter, referred to as “active compound 159”).

Active Compound 159

¹H-NMR (CDCl₃) δ: 10.57 (s, 1H), 8.79-8.78 (m, 1H), 8.67 (s, 1H),8.41-8.39 (m, 2H), 7.91 (d, J=5.1 Hz, 1H)

Production Example 157

To a mixture of 0.26 g of4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g ofpotassium carbonate and 3 ml of DMF, 0.17 g of isopropyl iodide wasadded at room temperature and stirred while heating at 60° C. for 1.5hours. To the reaction solution, 38 mg of potassium carbonate and 47 mgof isopropyl iodide were added, and the reaction solution was stirredwhile heating at 60° C. for two hours. The reaction solution was cooledto room temperature, and then water was added to the reaction mixture,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with water and a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.16 g of2-(3-isopropoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 160”).

Active Compound 160

¹H-NMR (CDCl₃) δ: 8.73-8.71 (m, 1H), 8.60 (s, 1H), 8.43-8.41 (m, 1H),8.39-8.38 (m, 1H), 8.02 (d, J=5.1 Hz, 1H), 4.94-4.83 (m, 1H), 1.52 (d,J=6.1 Hz, 6H)

Production Example 158

To a mixture of 0.25 g of4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g ofpotassium carbonate and 3 ml of DMF, a mixture of 0.15 g of ethyl iodideand 1 ml of DMF was added at room temperature and stirred while heatingat 60° C. for 1.5 hours. To the reaction mixture, 70 mg of potassiumcarbonate and 53 mg of iodoethane were added, and the reaction solutionwas stirred while heating at 60° C. for 3.5 hours. The reaction solutionwas cooled to room temperature, and then water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 60 mg of2-(3-ethoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 161”).

Active Compound 161

¹H-NMR (CDCl₃) δ: 8.74-8.72 (m, 1H), 8.60 (s, 1H), 8.45 (d, J=4.9 Hz,1H), 8.40-8.38 (m, 1H), 8.04-8.02 (m, 1H), 4.41 (q, J=6.9 Hz, 2H), 1.60(t, J=7.0 Hz, 3H)

Production Example 159

To a mixture of 0.31 g of4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g ofpotassium carbonate and 3 ml of DMF, a mixture of 0.50 g oftrifluoromethanesulfonate (2,2-difluoroethyl)ester and 7 ml of DMF wasadded at room temperature, and then stirred while heating at 60° C. forsix hours. The reaction mixture was cooled to room temperature, and thenwater was added to the reaction mixture, followed by extraction withethyl acetate twice. The combined organic layers were washed with waterand a saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.10 g of2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine(hereinafter, referred to as “active compound 162”).

Active Compound 162

¹H-NMR (CDCl₃) δ: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz,1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H)

Next, Production Examples for producing production intermediates of theabove-mentioned active compounds are described.

Reference Production Example 1

To a mixture of 5.0 g of 4-propylphenol and 35 ml of acetic acid, amixture of 3.80 g of 61% nitric acid and 10 ml of acetic acid was addeddropwise with the temperature kept at 10-15° C., which was stirred forfour hours. The reaction mixture was poured into ice water and extractedwith ethyl acetate. The combined organic layers were washed with water,a saturated aqueous solution of sodium hydrogencarbonate and a saturatedsodium chloride solution, dried over magnesium sulfate, and thenconcentrated under reduced pressure to give 6.65 g of4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 10.46 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.40 (dd,J=8.5, 2.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 2.58 (t, J=7.8 Hz, 2H),1.69-1.59 (m, 2H), 0.94 (t, J=7.3 Hz, 3H)

A mixture of 6.65 g of 4-propyl-2-nitrophenol, 55 ml of ethyl acetateand 1.0 g of 5% palladium on carbon was stirred under about oneatmosphere of hydrogen at room temperature for two hours. The mixturewas filtered through Celite™. The filtrate was concentrated underreduced pressure to give 5.17 g of 2-amino-4-propylphenol.

¹H-NMR (CDCl₃) δ: 6.64 (d, J=7.9 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 6.49(dd, J=8.0, 2.0 Hz, 1H), 3.74 (br s, 2H), 2.44 (t, J=7.8 Hz, 2H),1.63-1.52 (m, 2H), 0.91 (t, J=7.3 Hz, 3H)

Reference Production Example 2

4-butyl-2-nitrophenol was obtained according to the same manner as thatof Reference Production Example 1 using 4-butylphenol instead of4-propylphenol.

¹H-NMR (CDCl₃) δ: 10.46 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.41 (dd,J=8.5, 2.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 2.60 (t, J=7.6 Hz, 2H),1.65-1.53 (m, 2H), 1.41-1.30 (m, 2H), 0.93 (t, J=7.3 Hz, 3H)

2-amino-4-butylphenol was obtained according to the same manner as thatof Reference Production Example 1, using 4-butyl-2-nitrophenol insteadof 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 6.64 (d, J=8.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 6.49(dd, J=8.0, 2.0 Hz, 1H), 3.60 (br s, 2H), 2.47 (t, J=7.6 Hz, 2H),1.59-1.49 (m, 2H), 1.38-1.27 (m, 2H), 0.91 (t, J=7.3 Hz, 3H)

Reference Production Example 3

A mixture of 7 g of 4-methoxy-2-nitrophenol, 50 ml of ethyl acetate and1.3 g of 5% palladium on carbon was stirred under about one atmosphereof hydrogen at room temperature for 3.3 hours. The reaction mixture wasfiltered through Celite™. The filtrate was concentrated under reducedpressure to give 2-amino-4-methoxyphenol. This is used in the followingreaction without purification.

A mixture of 2.5 g of a crude product of 2-amino-4-methoxyphenol, 3.2 gof isonicotinic acid chloride hydrochloride and 20 ml of pyridine washeated to reflux for 12 hours. The reaction mixture was poured into icewater, and precipitated deposits are collected by filtration. Theobtained solid was dissolved in ethyl acetate, washed with water and asaturated sodium chloride solution, and dried over magnesium sulfate.Activated carbon was added thereto, followed by filtration throughCelite™. The filtrate was concentrated under reduced pressure to giveN-(2-hydroxy-5-methoxyphenyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.50 (br s, 8.79-8.75 (m, 2H), 7.89-7.83 (m, 2H),7.36-7.30 (m, 1H), 6.87-6.81 (m, 1H), 6.70-6.64 (m, 1H), 3.69 (s, 3H)

Reference Production Example 4

4-ethyl-2-nitrophenol was obtained according to the same manner as thatof Reference Production Example 1, using 4-ethylphenol instead of4-propylphenol.

¹H-NMR (CDCl₃) δ: 10.46 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.43 (dd,J=8.5, 2.2 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 2.64 (q, J=7.8 Hz, 2H), 1.25(t, J=7.8 Hz, 3H)

2-amino-4-ethylphenol was obtained according to the same manner as thatof Reference Production Example 1, using 4-ethyl-2-nitrophenol insteadof 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 6.65 (d, J=8.0 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H),6.53-6.49 (m, 1H), 3.84 (br s, 2H), 2.51 (q, J=7.6 Hz, 2H), 1.18 (t,J=7.6 Hz, 3H)

Reference Production Example 5

4-isopropyl-2-nitrophenol was obtained according to the same manner asthat of Reference Production Example 1, using 4-isopropylphenol insteadof 4-propylphenol.

¹H-NMR (CDCl₃) δ: 10.46 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.47 (dd,J=8.5, 2.2 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 2.97-2.86 (m, 1H), 1.25 (d,J=7.0 Hz, 6H)

2-amino-4-isopropylphenol was obtained according to the same manner asthat of Reference Production Example 1, using 4-isopropyl-2-nitrophenolinstead of 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 6.66 (d, J=8.2 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.54(dd, J=8.0, 2.2 Hz, 1H), 4.60 (br s, 1H), 3.58 (br s, 2H), 2.84-2.70 (m,1H), 1.19 (d, J=7.0 Hz, 6H)

Reference Production Example 6

4-tert-butyl-2-nitrophenol was obtained according to the same manner asthat of Reference Production Example 1, using 4-tert-butylphenol insteadof 4-propylphenol.

¹H-NMR (CDCl₃) δ: 10.47 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.64 (dd,J=8.8, 2.4 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 1.33 (s, 9H)

2-amino-4-tert-butylphenol was obtained according to the same manner asthat of Reference Production Example 1, using 4-tert-butyl-2-nitrophenolinstead of 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 6.80 (d, J=2.2 Hz, 1H), 6.70 (dd, J=8.2, 2.2 Hz, 1H),6.66 (d, J=8.2, 1H), 3.59 (br s, 2H), 1.26 (s, 9H)

Reference Production Example 7

2-amino-4-trifluoromethylphenol was obtained according to the samemanner as that of Reference Production Example 1, using2-nitro-4-trifluoromethylphenol instead of 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 6.98 (d, J=2.2 Hz, 1H), 6.95-6.92 (m, 1H), 6.76 (d,J=8.3, 1H), 5.33 (br s, 1H), 3.80 (br s, 2H)

A mixture of 2.84 g of 2-amino-4-trifluoromethylphenol, 1.97 g ofisonicotinic acid, 3.69 g of WSC[1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and 20 mlof pyridine was stirred while heating at 80° C. for four hours. Thereaction mixture was cooled to room temperature, and then water waspoured, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over magnesium sulfate, and then concentrated underreduced pressure. The residue was washed with an ethyl acetate-hexanemixture solvent to give 1.69 g ofN-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.82 (br s, 1H), 9.94 (br s, 1H), 8.80-8.78 (m,2H), 8.05 (d, J=2.0 Hz, 1H), 7.88-7.86 (m, 2H), 7.43 (dd, J=8.5, 2.0 Hz,1H), 7.10 (d, J=8.6 Hz, 1H)

Reference Production Example 8

To a mixture of 5 g of 3-tert-butylphenol and 30 ml of acetic acid, amixture of 3.0 g of 70% nitric acid and 10 ml of acetic acid was addeddropwise with the temperature kept at 10-15° C. and stirred for twohours. The reaction mixture was poured into ice water and extracted withethyl acetate twice. The combined organic layers were washed with water,a saturated aqueous solution of sodium hydrogencarbonate and a saturatedsodium chloride solution, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 1.82 g of 5-tert-butyl-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 10.60 (s, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.13 (d, J=2.2,1H), 7.01 (dd, J=9.0, 2.0 Hz, 1H), 1.33 (s, 9H)

2-amino-5-tert-butylphenol was obtained according to the same manner asthat of Reference Production Example 1, using 5-tert-butyl-2-nitrophenolinstead of 4-propyl-2-nitrophenol.

A mixture of 1.44 g of 2-amino-5-tert-butylphenol, 1.07 g ofisonicotinic acid, 2.17 g of WSC and 15 ml of pyridine was stirred whileheating at 80° C. for five hours. The reaction mixture was cooled toroom temperature, and then water was poured. Precipitated solid wasfiltered and washed with water and diethyl ether to give 1.22 g ofN-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 9.32 (br s, 1H), 9.12 (br s, 1H), 8.81-8.77(m, 2H), 7.85-7.78 (m, 3H), 7.03 (d, J=1.9, 1H), 6.93 (dd, J=8.5, 1.9Hz, 1H), 1.31 (s, 9H)

Reference Production Example 9

To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was addeddropwise at room temperature and the reaction mixture was stirred forone hour. The reaction mixture was poured into an ice-cooled saturatedaqueous solution of sodium hydrogencarbonate, followed by extractionwith ethyl acetate twice. The combined organic layers washed with waterand a saturated sodium chloride solution, dried over magnesium sulfate,and concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography to give 1.56 g of2-nitro-5-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 10.59 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.48-7.46 (m,1H), 7.27-7.23 (m, 1H)

2-amino-5-trifluoromethylphenol was obtained according to the samemanner as that of Reference Production Example 1, using2-nitro-5-trifluoromethylphenol instead of 4-propyl-2-nitrophenol.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 9.03 (br s, 1H), 7.01 (d, J=1.8 Hz, 1H),6.95-6.91 (m, 1H), 6.71-6.66 (m, 1H), 4.13 (br s, 2H)

A mixture of 1.30 g of 2-amino-5-trifluoromethylphenol, 0.9 g ofisonicotinic acid, 1.83 g of WSC and 15 ml of pyridine was stirred whileheating at 80° C. for three hours. The mixture was cooled to roomtemperature, and then water was poured. Precipitated solid was filteredand washed with water, and then dried under reduced pressure to give 1.5g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 8.82-8.76 (m, 2H), 7.98-7.93 (m, 1H), 7.89-7.85 (m,2H), 7.23-7.17 (m, 2H)

Reference Production Example 10

A mixture of 6.8 g of1,1,3,3-tetrafluoro-5-hydroxy-6-nitro-1,3-dihydroisobenzofuran and 20 mlof acetic acid was added dropwise to a mixture, which was heated to 80°C., of 7.8 g of electrolytic iron, 20 ml of acetic acid and 20 ml ofwater, and then the reaction mixture was stirred for one hour. Themixture was cooled to room temperature, and then water was added,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with water, a saturated aqueous solution of sodiumhydrogencarbonate, and a saturated sodium chloride solution, and driedover magnesium sulfate. Activated carbon was added, followed byfiltration through Celite™. The filtrates were concentrated underreduced pressure to give 4.43 g of6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran.

¹H-NMR (DMSO-d₆) δ: 10.65 (br s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 5.70(br s, 2H)

A mixture of 2.0 g of6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 1.1 g ofisonicotinic acid, 2.23 g of WSC and 15 ml of pyridine was stirred whileheating at 80° C. for three hours. The reaction mixture was cooled toroom temperature, and then water was poured into the reaction mixture.Precipitated solid was filtered and washed with water and dried underreduced pressure to give 1.34 g ofN-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.07 (br s, 1H), 8.80 (dd, J=4.4, 1.5 Hz, 2H), 8.36(s, 1H), 7.87 (dd, J=4.4, 1.5 Hz, 2H), 7.28 (s, 1H)

Reference Production Example 11

A mixture of 1 g of 3,5-dichloroisonicotinic acid and 5 ml of thionylchloride was heated to reflux for seven hours. Then, the mixture wascooled to room temperature, and then concentrated under reducedpressure. The residue was dissolved in 3 ml of DMF, which was addeddropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMFand 1.05 g of triethylamine at 0° C. The reaction mixture was stirred atroom temperature for two hours, and then water was added thereto,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with water and a saturated sodium chloride solution,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was washed with diethyl ether to give 0.75 g of3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide.

¹H-NMR (CDCl₃+DMSO-d₆) δ: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H)

Reference Production Example 12

A mixture of 0.89 g of 2-amino-4-(trifluoromethyl)phenol, 0.71 g of3-chloro-4-pyridinecarboxyaldehyde and 5 ml of ethanol was heated toreflux for three hours. The reaction mixture was concentrated and theresidue was washed with an ethyl acetate-hexane mixture solvent to give0.71 g of2-(3-chloropyridin-4-yl)methylideneamino-4-(trifluoromethyl)phenol.

¹H-NMR (CDCl₃) δ: 9.14 (s, 1H), 8.76 (s, 1H), 8.65 (d, J=5.1 Hz, 1H),8.01 (d, J=5.1 Hz, 1H), 7.62 (m, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.35 (brs, 1H), 7.14 (d, J=8.6 Hz, 1H)

Reference Production Example 13

To a mixture of 1.77 g of 2-amino-4-(trifluoromethyl)phenol, 1.58 g of3-chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was addedand stirred while heating at 60° C. for four hours. The reaction mixturewas cooled to room temperature, and then concentrated under reducedpressure. Water was added to the residue, followed by extraction withethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The residue was washedwith a mixture solvent of tert-butyl methyl ether and hexane to give1.80 g of3-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.89 (br s, 1H), 10.19 (br s, 1H), 8.75 (s, 1H),8.64 (d, J=4.9 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.63 (d, J=4.9 Hz, 1H),7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H)

Reference Production Example 14

To a mixture of 0.71 g of 2-amino-4-(trifluoromethyl)phenol, 0.63 g of2-chloroisonicotinic acid and 7 ml of pyridine, 1.05 g of WSC was addedand stirred while heating at 60° C. for four hours. The reaction mixturewas cooled to room temperature, and then concentrated under reducedpressure. Water was added to the residue, followed by extraction withethyl acetate twice. The combined organic layers were washed with asaturated sodium chloride solution, dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The residue was subjectedto silica gel column chromatography to give 0.77 g of2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.12 (br s, 1H), 8.62 (d, J=5.1 Hz, 1H), 8.03-7.97(m, 2H), 7.87 (dd, J=5.2, 1.3 Hz, 1H), 7.46-7.43 (m, 1H), 7.10 (d, J=8.2Hz, 1H)

Reference Production Example 15

A mixture of 0.62 g of 2-amino-4-(trifluoromethyl)phenol, 0.48 g of3-methyl isonicotinic acid, 0.86 g of WSC and 5 ml of pyridine wasstirred while heating at 60° C. for three hours. The reaction mixturewas cooled to room temperature, and then the reaction mixture wasconcentrated. Water was poured into the residue, followed by extractionwith ethyl acetate. The organic layer was washed with water and asaturated sodium chloride solution, sequentially. The organic layer wasdried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was washed with a mixture solvent of tert-butylmethyl ether and hexane to give 0.38 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-methylisonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.83 (br s, 1H), 8.55 (s, 1H), 8.52 (d, J=5.1 Hz,1H), 8.18 (s, 1H), 7.47 (d, J=5.1 Hz, 1H), 7.40 (dd, J=8.8, 1.9 Hz, 1H),7.06 (d, J=8.8 Hz, 1H), 2.39 (s, 3H)

Reference Production Example 16

While a mixture of 3.54 g of diisopropylamine and 50 ml oftetrahydrofuran was cooled in a dry ice-acetone bath, 20 ml of 1.6 Mhexane solution of n-butyllithium was added while stirring so that thetemperature of the reaction mixture did not exceed −40° C. Thereafter,the reaction mixture was stirred for 30 minutes. Then, a mixture of 2.91g of 3-fluoropyridine and 3 ml of tetrahydrofuran was added so that thetemperature of the reaction mixture did not exceed −60° C. The mixturewas further stirred for 30 minutes. After crushed dry ice was added tothe reaction mixture, cooling was stopped. Then, the reaction mixturewas stirred until the temperature returned to room temperature. Waterwas added to the reaction mixture, and most part of hexane andtetrahydrofuran was removed under reduced pressure. The residue waswashed with tert-butyl methyl ether, and the aqueous layers werecollected. To the collected aqueous layer, concentrated hydrochloricacid was added while ice-cooling, and pH of the mixture was made to be 3and stirred for one hour. Precipitates were collected by filtration anddried under reduced pressure to give 3.59 g of 3-fluoroisonicotinicacid.

¹H-NMR (DMSO-d₆) δ: 8.74 (d, J=2.4 Hz, 1H), 8.58 (d, J=4.9 Hz, 1H),7.80-7.77 (m, 1H)

Reference Production Example 17

A mixture of 0.49 g of 3-fluoroisonicotinic acid, 0.62 g of2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridinewas stirred while heating at 80° C. for two hours. The reaction mixturewas cooled to room temperature, and then concentrated. Water was pouredinto the residue, followed by extraction with ethyl acetate. The organiclayer was washed with a saturated sodium chloride solution. The organiclayer was dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The residue was washed with a tert-butyl methylether-hexane mixture solvent to give 0.51 g of3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 11.09 (s, 1H), 9.98 (br s, 1H), 8.76 (m, 1H), 8.60(d, J=4.6 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 7.78-7.75 (m 1H), 7.41 (dd,J=8.6, 2.2 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H)

Reference Production Example 18

A mixture of 3.54 g of diisopropylamine and 50 ml of tetrahydrofuran wasstirred while cooling in a dry ice-acetone bath. To the reactionmixture, 20 ml of 1.6 M hexane solution of n-butyllithium was added sothat the temperature of the reaction mixture did not exceed −40° C. Thereaction mixture was stirred for 30 minutes. Then, a mixture of 4.74 gof 3-bromopyridine and 5 ml of tetrahydrofuran was added so that thetemperature of the reaction mixture did not exceed −60° C. The reactionmixture was stirred for further 30 minutes. Crushed dry ice was added tothe reaction mixture and then cooling was stopped. The reaction mixturewas stirred until the temperature retuned to room temperature. Water wasadded thereto, most of hexane and tetrahydrofuran was removed underreduced pressure. The residue was washed with tert-butyl methyl ether,and the aqueous layers were collected. To the collected aqueous layers,concentrated hydrochloric acid was added while ice-cooling so that pH ofthe mixture was made to be 3 and stirred for one hour, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with a saturated sodium chloride solution, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive 0.69 g of 3-bromo isonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 8.74 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 7.69 (d, J=4.9Hz, 1H)

Reference Production Example 19

A mixture of 0.69 g of 3-bromo isonicotinic acid, 0.60 g of2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridinewas stirred while heating at 80° C. for two hours. The reaction mixturewas cooled to room temperature, and then concentrated. Water was addedto the residue, followed by extraction with ethyl acetate. The organiclayer was washed with a saturated sodium chloride solution, then driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was washed with a mixture solvent of ethyl acetate andhexane to give 0.29 g of3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.

Reference Production Example 20

Water was added to 3.20 g of sodium hydroxide to make 30 ml of aqueoussolution in total. To the solution, 5.83 g of 3-iodo-isonicotinic acidmethyl ester (U.S. Pat. No. 6,277,871B1, O'Conner et al.) was added. Themixture solution was stirred while heating at 60° C. for three hours.The reaction mixture was cooled in ice, to which concentratedhydrochloric acid was added to adjust pH to 2-3. Precipitates werecollected by filtration and dried under reduced pressure to give 5.21 gof 3-iodo-isonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 9.04 (s, 1H), 8.64 (d, J=5.1 Hz, 1H), 7.65 (d, J=5.1Hz, 1H)

Reference Production Example 21

A mixture of 1.78 g of 3-iodo-isonicotinic acid, 1.38 g of WSC and 12 mlof pyridine was stirred while heating at 50° C. for 15 minutes. Then,1.15 g of 2-amino-4-(trifluoromethyl)phenol was added to the reactionmixture. The reaction mixture was stirred while heating at 80° C. fortwo hours. The reaction mixture was returned to room temperature, andconcentrated under reduced pressure. Water was added to the residue,followed by extraction with ethyl acetate. The organic layer was washedwith a saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure to give 1.81 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3iodo isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.85 (br s, 1H), 10.09 (br s, 1H), 8.97 (s, 1H),8.64-8.62 (m, 1H), 8.29-8.27 (m, 1H), 7.54-7.51 (m, 1H), 7.42-7.38 (m,1H), 7.07 (d, J=8.5 Hz, 1H)

Reference Production Example 22

To a mixture of 3.69 g of nicotinic acid and 30 ml of toluene, 3.64 g ofdiisopropylethylamine, then 8.67 g of diphenylphosphoryl azide wasadded. The reaction mixture was stirred at room temperature for 30minutes. To the reaction mixture, 4 ml of tert-butyl alcohol was added.The reaction mixture was stirred while heating at 80° C. for six hours.The reaction mixture was cooled to room temperature, then the reactionmixture was diluted with ethyl acetate, washed with water and then witha saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue was washedwith a mixture solvent of ethyl acetate and hexane to give 4.07 g of3-(tert-butoxycarbonyl amino)pyridine.

¹H-NMR (CDCl₃) δ: 8.46 (d, J=2.7 Hz, 1H), 8.28 (dd, J=4.9, 1.2 Hz, 1H),8.03-7.96 (m, 1H), 7.25-7.21 (m, 1H), 7.04 (br s, 1H), 1.53 (s, 9H)

While a mixture of 1.16 g of 3-(tert-butoxycarbonylamino)pyridine and 25ml of tetrahydrofuran was cooled in a dry ice-acetone bath, 8.5 ml of1.65 M hexane solution of n-butyllithium was added so that thetemperature of the reaction mixture did not exceed −60° C. The reactionmixture was stirred for 15 minutes. Cooling was stopped. Then, thereaction mixture was stirred until the temperature became 0° C. Thereaction mixture was cooled in a dry ice-acetone bath again. Afterinjection of carbon dioxide, cooling was stopped, and the reactionmixture was stirred at room temperature for two hours. After water wasadded, most of tetrahydrofuran and hexane was removed by concentrationunder reduced pressure. The residue was ice-cooled and 3N hydrochloricacid was added so as to adjust pH to about 3. Extraction with a mixturesolvent (4:1) of ethyl acetate to tetrahydrofuran was carried outseveral times. The combined organic layers were washed with a saturatedsodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give 0.53 g of3-(tert-butoxycarbonyl amino)isonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 10.07 (s, 1H), 9.37 (s, 1H), 8.35 (d, J=5.1 Hz, 1H),7.76 (d, J=5.1 Hz, 1H), 1.49 (s, 9H)

To a mixture of 1.15 g of WSC and 8 ml of pyridine, 1.43 g of3-tert-butoxycarbonylamino isonicotinic acid was added and stirred atroom temperature for 15 minutes. To the reaction mixture, 1.06 g of2-amino-4-(trifluoromethyl)phenol was added and stirred while heating at60° C. for two hours. Thereafter, the mixture reaction was cooled toroom temperature, and then concentrated under reduced pressure. Waterwas added to the residue, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated sodiumchloride solution, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give 1.79 g of3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.

Reference Production Example 23

To a mixture of 5.0 g of 60% sodium hydride (in oil) and 70 ml of DMF, amixture of 4-iodophenol and 25 ml of DMF was added dropwise whileice-cooling, and stirred for one hour. The temperature was increased toroom temperature, a mixture of 12.9 g of chloromethyl ethyl ether and 10ml of DMF was added dropwise, and stirred for further one hour. Thereaction mixture was poured into ice water, and extracted with ethylacetate three times. The combined organic layers was washed with waterand a saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to give 32 g of a crudeproduct of 1-ethoxymethoxy-4-iodobenzene. The crude product was used forthe next reaction without purification.

A mixture of 7.5 g of crude product of 1-ethoxymethoxy-4-iodobenzene,10.0 g of sodium pentafluoropropionate salt, 10.27 g of copper (I)iodide, 120 ml of DMF and 45 ml of toluene was stirred while heating at140 to 150° C. for one hour to remove about 40 ml of toluene. Thereaction mixture was heated to reflux at 160 to 170° C. for further fivehours, and then cooled to room temperature and poured into ice water. Tothe reaction mixture, 200 ml of diethyl ether was added. The reactionmixture was filtered through Celite™. The filtrate was extracted withdiethyl ether. The combined organic layers were washed with water and asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to give 5.45 g of1-ethoxymethoxy-4-pentafluoroethyl benzene.

¹H-NMR (CDCl₃) δ: 7.51 (d, J=8.9 Hz, 2H), 7.13 (d, J=8.9 Hz, 2H), 5.27(s, 2H), 3.73 (q, J=7.0 Hz, 2H), 1.23 (t, J=7.0, 3H)

7.39 g of 1-ethoxymethoxy-4-pentafluoroethyl benzene, 30 ml of acetoneand 30 ml of 6 M hydrochloric acid were stirred while heating at 50° C.for 2.5 hours. The reaction mixture was cooled to room temperature, andthen poured into water, followed by extraction with ethyl acetate. Thecombined organic layers were washed with water and a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 4-(pentafluoroethyl)phenol.

¹H-NMR (CDCl₃) δ: 7.47 (d, 8.5 Hz, 2H), 6.93 (d, 8.5 Hz, 2H), 5.74 (brs, 1H)

To a mixture of 1.70 g of 4-(pentafluoroethyl)phenol, 6 ml of aceticacid and 2.0 ml of concentrated sulfuric acid, a mixture of 0.80 g of69% nitric acid and 1 ml of acetic acid was added dropwise whileice-cooling, and stirred at room temperature for three hours. Thereaction mixture was poured into ice water, followed by extraction withethyl acetate three times. The combined organic layers were washed withwater and a saturated sodium chloride solution, dried over sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 1.40 g of4-(pentafluoroethyl)-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 10.02 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.79 (dd,J=9.0, 2.0 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H)

A mixture of 1.38 g of 4-(pentafluoroethyl)-2-nitrophenol, 15 ml ofethyl acetate and 0.15 g of 5% palladium on carbon was stirred underabout one atmosphere of hydrogen at room temperature for four hours. Thereaction mixture was filtered through Celite™. The filtrate wasconcentrated under reduced pressure. The residue was washed with hexaneto give 1.02 g of 2-amino-4-(pentafluoroethyl)phenol.

¹H-NMR (CDCl₃) δ: 6.94 (s, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.3Hz, 1H), 5.34 (br s, 1H), 3.82 (br s, 2H)

To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.28 g ofisonicotinic acid was added, and the reaction mixture was stirred atroom temperature for 15 minutes. To the reaction mixture, 0.45 g of2-amino-4-(pentafluoroethyl)phenol that had been obtained in theabove-mentioned reaction was added and stirred while heating at 60° C.for two hours. The reaction mixture was cooled to room temperature, andthe concentrated under reduced pressure. Water was added to the residue,followed by extraction with ethyl acetate twice. The combined organiclayers were washed with water and a saturated sodium chloride solution,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.50 g ofN-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.89 (br s, 1H), 9.93 (br s, 1H), 8.79 (d, J=5.4Hz, 2H), 8.03 (d, J=2.0 Hz, 1H), 7.88 (d, J=5.6 Hz, 2H), 7.39 (dd,J=8.5, 2.0 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H)

Reference Production Example 24

To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of3-chloroisonicotinic acid was added. The reaction mixture was stirred atroom temperature for 15 minutes. To the reaction mixture, 0.45 g of2-amino-4-(pentafluoroethyl)phenol was added and stirred while heatingat 60° C. for two hours. The reaction mixture was cooled to roomtemperature, and then concentrated under reduced pressure. Water wasadded to the residue, followed by extraction with ethyl acetate twice.The combined organic layers were washed with water and a saturatedsodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.25 g of3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H),8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H),7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H)

Reference Production Example 25

To a mixture of 3.92 g of 4-(heptafluoroisopropyl)aniline, 20 ml ofacetic acid, 3.0 g of concentrated sulfuric acid and 3 ml of water, anaqueous solution of 1.14 g of sodium nitrite was gradually addeddropwise while ice-cooling, and stirred for 30 minutes whileice-cooling, and the stirred while heating at 80° C. for one hour. Thereaction mixture was cooed to room temperature, and then the reactionmixture was poured into water, followed by extraction with ethyl acetatethree times. The combined organic layers were washed with a saturatedsodium chloride solution, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 3.60 g of mixture containing4-(heptafluoroisopropyl)phenol.

¹H-NMR (CDCl₃) δ: 7.48 (d, J=8.9 Hz, 2H), 6.96-6.92 (m, 2H), 5.64 (br s,1H)

To a mixture of 3.60 g of mixture containing4-(heptafluoroisopropyl)phenol, 8 ml of acetic acid, and 2.5 g ofconcentrated sulfuric acid, a mixture of 1.05 g of 69% nitric acid and 1ml of acetic acid was added dropwise while ice-cooling, and then stirredat room temperature for two hours. The reaction mixture was poured intowater, and extracted with ethyl acetate three times. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 2.96 g of 4-(heptafluoroisopropyl)-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 10.76 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.79 (dd,J=9.0, 2.0 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H)

A mixture of 2.95 g of 4-(heptafluoroisopropyl)-2-nitrophenol, 20 ml ofethyl acetate and 0.30 g of 5% palladium on carbon was stirred in ahydrogen atmosphere at room temperature for four hours. The reactionmixture was filtered through Celite™. The filtrate was concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 2.08 g of 2-amino-4-(heptafluoroisopropyl)phenol.

¹H-NMR (CDCl₃) δ: 6.96 (s, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6Hz, 1H), 5.38 (br s, 1H), 3.84 (br s, 2H)

To a mixture of 0.58 g of WSC and 5 ml of pyridine, 0.37 g ofisonicotinic acid was added. The reaction mixture was stirred at roomtemperature for 25 minutes. To the reaction mixture, 0.75 g of2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred whileheating at 60° C. for three hours. The mixture was cooled to roomtemperature, and then concentrated under reduced pressure. Then, waterwas added to the residue, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with water and asaturated sodium chloride solution, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography to give 0.79 g ofN-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.83 (br s, 1H), 9.92 (br s, 1H), 8.80-8.78 (m,2H), 8.06 (br s, 1H), 7.88-7.86 (m, 2H), 7.36 (dd, J=8.8, 2.0 Hz, 1H),7.15 (d, J=8.8 Hz, 1H)

Reference Production Example 26

To a mixture of 0.58 g of WSC and 5 ml of pyridine 5 ml, 0.48 g of3-chloroisonicotinic acid was added. The reaction mixture was stirred atroom temperature for 25 minutes. To the reaction mixture, 0.75 g of2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred whileheating at 60° C. for three hours. The reaction mixture was cooled toroom temperature, the 0.24 g of 3-chloroisonicotinic acid and 0.29 g ofWSC was added and stirred while heating at 60° C. for 1.5 hours and thenat 80° C. for 1.3 hours. The mixture reaction was cooled to roomtemperature, and then concentrated under reduced pressure. Then, waterwas added to the residue, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated sodiumchloride solution, was dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.90 g of3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz,1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J=8.8,2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H)

Reference Production Example 27

To a mixture of 3.78 g of 2-chloro-4-(trifluoromethyl)phenol, 12 ml ofacetic acid and 3 ml of concentrated sulfuric acid, a mixture of 21.5 gof 69% nitric acid and 2 ml of acetic acid was added while ice-cooling.The reaction mixture was stirred while heating at room temperature for30 minutes and then at 60° C. for two hours. After the reaction mixturewas cooled to room temperature, then the reaction mixture was pouredinto water, and extracted with ethyl acetate three times. The combinedorganic layers were washed with saturated sodium chloride solution,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 5.01 g of a mixture containing2-chloro-6-nitro-4-(trifluoromethyl)phenol.

¹H-NMR (CDCl₃) δ: 11.26 (br s, 1H), 8.36 (m, 1H), 7.95 (d, J=2.2 Hz, 1H)

A mixture of 5.01 g of a mixture containing2-chloro-4-(trifluoromethyl)-6-nitrophenol, 15 ml of ethyl acetate and1.0 g of 5% palladium on carbon was stirred under about one atmosphereof hydrogen at room temperature for 15 hours. The mixture was filteredthrough Celite™. The filtrate was concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give2.78 g of 2-amino-6-chloro-4-(trifluoromethyl)phenol.

¹H-NMR (CDCl₃) δ: 7.00 (m, 1H), 6.84 (d, J=2.2 Hz, 1H), 5.80 (br s, 1H),4.05 (br s, 2H)

To a mixture of 0.58 g of WSC and 5 ml pyridine, 0.37 g of isonicotinicacid was added. The reaction mixture was stirred at room temperature for15 minutes. To the reaction mixture, 0.63 g of2-amino-6-chloro-4-(trifluoromethyl)phenol that had been obtained in theabove-mentioned reaction was added. The reaction mixture was stirredwhile heating at 60° C. for three hours. The reaction mixture was cooledto room temperature, and then concentrated under reduced pressure. Waterwas added to the residue, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with a saturated sodiumchloride solution, then dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was washed with amixture solvent of tert-butyl methyl ether and hexane to give 0.42 g ofN-[3-chloro-5-(trifluoromethyl)-2-hydroxyphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.27 (br s, 1H), 8.81-8.79 (m, 2H), 7.90-7.88 (m,2H), 7.86 (d, J=2.0 Hz, 1H), 7.68-7.67 (m, 1H)

Reference Production Example 28

To a mixture of 4.0 g of 4-trifluoromethoxy phenol and 25 ml of aceticacid, a mixture of 2.02 g of 70% nitric acid and 10 ml of acetic acidwas added dropwise with the temperature kept at 10-15° C. The reactionmixture was stirred for five hours. The reaction mixture was poured intoice water and extracted with ethyl acetate. The combined organic layerswere washed with water, a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution, dried oversodium sulfate, and then concentrated under reduced pressure to give4.53 g of 4-trifluoromethoxy-2-nitrophenol.

¹H-NMR (CDCl₃) δ: 10.50 (s, 1H), 8.02-7.99 (m, 1H), 7.50-7.45 (m, 1H),7.22 (d, J=9.1 Hz, 1H)

A mixture of 4.53 g of 4-trifluoromethoxy-2-nitrophenol, 35 ml of ethylacetate and 1.0 g of 5% palladium on carbon was stirred under about oneatmosphere of hydrogen at room temperature for 1.7 hours. The mixturewas filtered through Celite™. The filtrate was concentrated underreduced pressure to give 3.92 g of 2-amino-4-trifluoromethoxy phenol.

To a mixture of 2.5 g of 2-amino-4-trifluoromethoxy phenol, 2.62 g oftriethylamine and 15 ml of DMF, 2.31 g of 4-isonicotinic acid chloridehydrochloride was added while ice-cooling. The reaction mixture wasstirred for 3.3 hours. The reaction mixture was poured into water andprecipitated crystals were filtered and dried under reduced pressure togive 2.19 g of N-[5-(trifluoromethoxy)-2-hydroxyphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 8.78 (dd, J=4.4, 1.7 Hz, 2H), 7.86 (dd, J=4.4, 1.6Hz, 2H), 7.80-7.77 (m, 1H), 7.10-7.05 (m, 1H), 6.99 (d, J=8.7 Hz, 1H)

Reference Production Example 29

A mixture of 0.41 g of 2-amino-4-tert-butylphenol, 0.35 g of3-chloro-4-pyridinecarboxyaldehyde and 2.5 ml of ethanol was heated toreflux for three hours. The reaction mixture was concentrated. Theresidue was subjected to silica gel column chromatography to give 0.50 gof 2-(3-chloropyridin-4-yl)methylideneamino-4-tert-butylphenol.

¹H-NMR (CDCl₃) δ: 9.07 (s, 1H), 8.71 (s, 1H), 8.60 (d, J=5.1 Hz, 1H),8.01 (d, J=5.1 Hz, 1H), 7.36-7.33 (m, 2H), 7.02 (s, 1H), 7.00-6.97 (m,1H), 1.35 (s, 9H)

Reference Production Example 30

To a mixture of 4.8 g of 4-(trifluoromethylthio)phenol and 20 ml ofacetic acid, a mixture of 2.5 g of 70% nitric acid and 1 ml of aceticacid and then 1.5 ml of concentrated sulfuric acid were added dropwisewith the internal temperature kept at 10-15° C. The reaction mixture wasstirred for three hours. The reaction mixture was poured into ice waterand extracted with ethyl acetate. The combined organic layers werewashed with water, a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution, dried overmagnesium sulfate, and then concentrated under reduced pressure to give5.94 g of 2-nitro-4-(trifluoromethylthio)phenol.

¹H-NMR (CDCl₃) δ: 10.78 (br s, 1H), 8.44 (s, 1H), 7.83 (d, J=8.8, 1H),7.24 (d, J=8.8 Hz, 1H)

A mixture of 5.49 g of 2-nitro-4-(trifluoromethylthio)phenol and 10 mlof ethyl acetate was added dropwise to a mixture, which was heated to80° C., of 6.4 g of electrolytic iron, 10 ml of acetic acid and 20 ml ofwater. The reaction mixture was stirred for 30 minutes. The mixture wascooled to room temperature, and then water was added, followed byextraction with ethyl acetate twice. The combined organic layers werewashed with water, a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 2.0 gof 2-amino-4-(trifluoromethylthio)phenol.

¹H-NMR (CDCl₃) δ: 7.04 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.0, 2.0 Hz, 1H),6.73 (d, J=8.0 Hz, 1H), 5.16 (br s, 1H), 3.74 (br s, 2H)

A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g ofWSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred whileheating at 80° C. for three hours. The reaction mixture was cooled toroom temperature, and then water was poured into the reaction mixture,followed by extraction with ethyl acetate three times. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 0.42 g ofN-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.89 (br s, 1H), 8.78 (dd, J=4.3, 1.7 Hz, 2H), 8.05(d, J=2.2 Hz, 1H), 7.87 (dd, J=4.3, 1.7 Hz, 2H), 7.42 (dd, J=8.5, 2.2Hz, 1H), 7.05 (d, J=8.5 Hz, 1H)

Reference Production Example 31

A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of3-chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine wasstirred while heating at 80° C. for three hours. The reaction mixturewas cooled to room temperature, and then water was added to the reactionmixture, followed by extraction with ethyl acetate three times. Thecombined organic layers were washed with water and a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.63 g of3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.89 (br s, 1H), 10.14 (br s, 1H), 8.74 (s, 1H),8.63 (d, J=4.8 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H),7.39 (dd, J=8.5, 2.2 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H)

Reference Production Example 32

To a mixture of 5.0 g of 4-chloro-3-trifluoromethylphenol and 20 ml ofacetic acid, 1.5 ml of concentrated sulfuric acid and then 2.6 g of 69%nitric acid were added dropwise while ice-cooling. To the reactionmixture, 3 ml of concentrated sulfuric acid was added dropwise at roomtemperature, and stirred for three hours. The reaction mixture waspoured into ice water, and extracted with ethyl acetate. The combinedorganic layers were washed with water, a saturated aqueous solution ofsodium hydrogencarbonate and a saturated sodium chloride solution, driedover magnesium sulfate, and then concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give2.3 g of 4-chloro-2-nitro-5-trifluoromethylphenol, 1.57 g of4-chloro-2-nitro-3-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 10.43 (s, 1H), 8.27 (s, 1H), 7.57 (s, 1H)

¹H-NMR (CDCl₃) δ: 7.53 (d, J=9.0 Hz, 1H), 7.24 (d, J=9.0 Hz, 1H)

A mixture of 2.3 g of 4-chloro-2-nitro 5-trifluoromethylphenol and 10 mlof ethyl acetate was added dropwise to a mixture, which was heated to80° C., of 2.6 g of electrolytic iron, 10 ml of acetic acid and 20 ml ofwater, and then the reaction mixture was stirred for one hour. Themixture was cooled to room temperature, and then water was added,followed by extraction with ethyl acetate. The combined organic layerswere washed with water, a saturated aqueous solution of sodiumhydrogencarbonate and a saturated sodium chloride solution, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography to give 1.7 gof 2-amino-4-chloro-5-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 6.99 (s, 1H), 6.77 (s, 1H), 5.01 (br s, 1H), 4.09 (brs, 2H)

A mixture of 0.70 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.79 gof WSC, 0.39 g of isonicotinic acid and 6 ml of pyridine was stirredwhile heating at 80° C. for three hours. The reaction mixture was cooledto room temperature, and then water was added, followed by extractionwith ethyl acetate three times. The combined organic layers were washedwith water and a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.54 g ofN-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.08 (br s, 1H), 8.80 (dd, J=4.3, 1.7 Hz, 2H), 8.13(s, 1H), 7.86 (dd, J=4.3, 1.7 Hz, 2H), 7.32 (s, 1H)

Reference Production Example 33

A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 gof 3-chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine wasstirred while heating at 80° C. for three hours. The reaction mixturewas cooled to room temperature, and then water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with water and a saturated sodium chloride solution, driedanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.67 g of3-chloro-N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.36 (s, 1H),7.62 (d, J=4.8 Hz, 1H), 7.28 (s, 1H)

Reference Production Example 34

A mixture of 1.57 g of 4-chloro-2-nitro-3-trifluoromethylphenol and 5 mlof ethyl acetate was added dropwise to a mixture, which was heated to80° C., of 1.8 g of electrolytic iron, 7 ml of acetic acid and 7 ml ofwater, which was stirred for 30 minutes. The mixture was cooled to roomtemperature, and then water was added, followed by extraction with ethylacetate. The combined organic layers were washed with water, a saturatedaqueous solution of sodium hydrogencarbonate and a saturated sodiumchloride solution, dried over magnesium sulfate, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 1.1 g of2-amino-4-chloro-3-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 6.72 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.48(br s, 1H), 4.67 (br s, 2H)

A mixture of 0.75 g of 2-amino-4-chloro-3-trifluoromethylphenol, 0.84 gof WSC, 0.42 g of isonicotinic acid and 5 ml of pyridine was stirredwhile heating at 80° C. for three hours. To the reaction mixture, 0.1 gof isonicotinic acid was added, and the reaction mixture was stirredwhile heating for further three hours. The reaction mixture was cooledto room temperature, and then water was added, followed by extractionwith ethyl acetate three times. The combined organic layers were washedwith water and a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.54 g ofN-[3-chloro-6-hydroxy-2-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.47 (br s, 1H), 10.20 (br s, 1H), 8.80 (dd, J=4.6,1.4 Hz, 2H), 7.85 (dd, J=4.6, 1.4 Hz, 2H), 7.51 (d, J=8.9 Hz, 1H), 7.22(d, J=8.9 Hz, 1H)

Reference Production Example 35

A mixture of 10 g of 2,4-dichloro-5-nitrobenzotrifluoride, 4.15 g ofpotassium acetate and 60 ml of DMF was stirred while heating at 60° C.for one hour and at 80° C. for three hours. To the reaction mixture,4.15 g of potassium acetate was added. The reaction mixture was stirredwhile heating at 80° C. for further one hour. The reaction mixture wascooled to room temperature, and 1 M hydrochloric acid was added thereto,followed by extraction with ethyl acetate. The combined organic layerswere washed with water and a saturated sodium chloride solution, driedover magnesium sulfate, and then concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give7.55 g of 5-chloro-2-nitro-4-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 10.81 (s, 1H), 8.49 (s, 1H), 7.37 (s, 1H)

A mixture of 7.55 g of 5-chloro-2-nitro-4-trifluoromethylphenol and 10ml of ethyl acetate was added dropwise to a mixture, which was heated to80° C., of 8.7 g of electrolytic iron, 30 ml of acetic acid and 50 ml ofwater, and then the reaction mixture was stirred at the same temperaturefor 30 minutes. The mixture was cooled to room temperature, and thenwater was added, followed by extraction with ethyl acetate. The combinedorganic layers were washed with water, a saturated aqueous solution ofsodium hydrogencarbonate and a saturated sodium chloride solution, driedover magnesium sulfate, and then concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give5.4 g of 2-amino-5-chloro-4-trifluoromethylphenol.

¹H-NMR (CDCl₃) δ: 7.03 (s, 1H), 6.84 (s, 1H), 5.93 (br s, 1H), 3.81 (brs, 2H)

A mixture of 1.2 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.35 gof WSC, 0.67 g of isonicotinic acid and 10 ml of pyridine was stirredwhile heating at 80° C. for three hours. The reaction mixture was cooledto room temperature, and then water was added, followed by extractionwith ethyl acetate three times. The combined organic layers were washedwith water and a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 1.01 g ofN-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.03 (br s, 1H), 8.79 (dd, J=4.3, 1.7 Hz, 2H), 8.14(s, 1H), 7.86 (dd, J=4.3, 1.7 Hz, 2H), 7.16 (s, 1H)

Reference Production Example 36

A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 gof 3-chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine wasstirred while heating at 80° C. for three hours. The reaction mixturewas cooled to room temperature, and then water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with water and a saturated sodium chloride solution, driedover anhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.46 g of3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.32 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz,1H), 8.43 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.13 (s, 1H)

Reference Production Example 37

A mixture of 0.68 g of6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 gof 3-chloroisonicotinic acid, 0.76 g of WSC and 7 ml of pyridine wasstirred while heating at 80° C. for three hours. The reaction mixturewas cooled to room temperature, and then water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with water and a saturated sodium chloride solution, thendried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 0.68 g of3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz,1H), 8.55 (s, 1H), 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H)

Reference Production Example 38

A mixture of 1.5 g of6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.95 gof 3-fluoroisonicotinic acid, 1.68 g of WSC and 13 ml of pyridine wasstirred while heating at 80° C. for two hours. The reaction mixture wascooled to room temperature, and then water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with water and a saturated sodium chloride solution, driedover anhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 1.46 g of3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.21 (br s, 1H), 8.79-8.77 (m, 1H), 8.63-8.58 (m,2H), 7.81-7.76 (m, 1H), 7.30 (s, 1H)

Reference Production Example 39

A mixture of 2.0 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.33 gof 3-fluoroisonicotinic acid, 2.36 g of WSC and 15 ml of pyridine wasstirred while heating at 80° C. for 3.5 hours. The reaction mixture wascooled to room temperature, and then water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with water and a saturated sodium chloride solution, thendried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 2.08 g of3-fluoro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 11.57 (br s, 1H), 10.08 (br s, 1H), 8.77-8.75 (m,1H), 8.61-8.58 (m, 1H), 8.48 (s, 1H), 7.78-7.73 (m, 1H), 7.15 (s, 1H)

Reference Production Example 40

A mixture of 0.62 g of 3-ethyl isonicotinic acid 4 ml of thionylchloride was heated to reflux for 2.5 hours. The reaction mixture wascooled to room temperature, the reaction mixture was concentrated underreduced pressure to give 3-ethyl isonicotinic acid chloride. A mixtureof the resultant 3-ethyl isonicotinic acid chloride and 3 ml of DMF wasadded dropwise to a mixture of 0.87 g of2-amino-5-chloro-4-trifluoromethylphenol, 0.83 g of triethylamine and 3ml of DMF while ice-cooling. The reaction mixture was stirred at roomtemperature for two hours, and then water was added to the reactionmixture, followed by extraction with ethyl acetate twice. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography to give 0.23 g ofN-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]-3-ethylisonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.98 (br s, 1H), 8.58-8.56 (m, 1H), 8.53 (d, J=4.8Hz, 1H), 8.25 (s, 1H), 7.45 (d, J=4.9 Hz, 1H), 7.11 (s, 1H), 2.76 (q,J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H)

Reference Production Example 41

A mixture of 0.69 g of 3-chloroisonicotinic acid, 5 ml of thionylchloride and 30 mg of DMF was heated to reflux for 3.5 hours. Thereaction mixture was cooled to room temperature, and then the reactionmixture was concentrated under reduced pressure to give3-chloroisonicotinic acid chloride. A mixture of the resultant3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise toa mixture of 0.85 g of 2-amino-5-fluoro-4-trifluoromethylphenol, 0.88 gof triethylamine and 4 ml of DMF while ice-cooling. Thereafter, thereaction mixture was stirred at room temperature for one hour and at 50°C. for one hour. The reaction mixture was cooled to room temperature,and then water was added, followed by extraction with ethyl acetatetwice. The combined organic layers wee washed with water and a saturatedsodium chloride solution, then dried over anhydrous magnesium sulfate,and then concentrated under reduced pressure. The resultant solid waswashed with diethyl ether to give 0.77 g of3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz,1H), 8.23 (d, J=8.5 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.91-6.85 (m, 1H)

Reference Production Example 42

3-chloro-N-[2-fluoro-6-hydroxy-3-(trifluoromethyl)phenyl]-isonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 41 using 2-amino-3-fluoro-4-trifluoromethylphenolinstead of 2-amino-5-fluoro-4-trifluoromethylphenol.

¹H-NMR (DMSO-d₆) δ: 11.15 (br s, 1H), 10.22 (br s, 1H), 8.79 (s, 1H),8.67 (d, J=4.6 Hz, 1H), 7.62 (d, J=4.6 Hz, 1H), 7.58-7.52 (m, 1H), 6.92(d, J=8.8 Hz, 1H)

Reference Production Example 43

A mixture of 0.17 g of 2-amino-3-chloro-4-trifluoromethylphenol, 0.99 gof isonicotinic acid, 0.19 g of WSC and 3 ml of pyridine was stirredwhile heating at 80° C. for two hours. The mixture was cooled to roomtemperature, and then water was poured, followed by extraction withethyl acetate three times. The combined organic layers were washed withwater and a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.15 g ofN-[2-chloro-6-hydroxy-3-(trifluoromethyl)pheny]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.98 (br s, 1H), 10.24 (br s, 1H), 8.82-8.79 (m,2H), 7.94-7.85 (m, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H)

Reference Production Example 44

3-ethyl-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 40 using6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran insteadof 2-amino-5-chloro-4-trifluoromethylphenol.

¹H-NMR (DMSO-d₆) δ: 10.10 (br s, 1H), 8.60-8.58 (m, 1H), 8.54 (d, J=4.9Hz, 1H), 8.44 (s, 1H), 7.45 (d, J=4.9 Hz, 1H), 7.26 (s, 1H), 2.77 (q,J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H)

Reference Production Example 45

A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionylchloride and 50 mg of DMF was heated to reflux for two hours. Thereaction mixture was cooled to room temperature, and then the reactionmixture was concentrated under reduced pressure to give3-fluoroisonicotinic acid chloride. A mixture of the resultant3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise toa mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g oftriethylamine and 10 ml of DMF while ice-cooling. The reaction mixturewas stirred at room temperature for 1.5 hours and at 50° C. for 30minutes. The reaction mixture was cooled to room temperature, and thenwater was added. Precipitated crystals were collected by filtration. Theresultant crystals were dissolved in ethyl acetate, washed with waterand a saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, concentrated under reduced pressure to give 2.41 g ofN-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.73 (br s, 1H), 8.76-8.74 (m, 1H), 8.61-8.58 (m,1H), 7.99 (d, J=2.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.06 (dd, J=8.5, 2.4 Hz,1H), 6.84 (d, J=8.5 Hz, 1H), 1.26 (s, 9H)

Reference Production Example 46

N-(5-tert-butyl-2-hydroxyphenyl)-3-ethyl isonicotinamide was obtainedaccording to the same manner as that of Reference Production Example 40using 2-amino-4-tert-butylphenol instead of2-amino-5-chloro-4-trifluoromethylphenol.

¹H-NMR (DMSO-d₆) δ: 9.66 (br s, 1H), 9.51 (br s, 1H), 8.58-8.56 (m, 1H),8.52 (d, J=4.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.45 (d, J=4.9 Hz, 1H),7.07 (dd, J=8.5, 2.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 2.79 (q, J=7.6 Hz,2H), 1.21 (t, J=7.6 Hz, 3H)

Reference Production Example 47

A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and4 ml of thionyl chloride was heated to reflux for 2.5 hours. Thereaction mixture was cooled to room temperature, and concentrated underreduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acidchloride. A mixture of the resultant 2-chloro-5-trifluoromethylisonicotinic acid chloride and 4 ml of DMF was added dropwise to amixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamineand 4 ml of DMF while ice-cooling. The reaction mixture was stirred atroom temperature for one hour, and stirred while heating at 50° C. forone hour. The mixture was cooled to room temperature, and water wasadded to the reaction mixture, followed by extraction with ethyl acetatetwice. The combined organic layers were washed with water and asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography to give 0.75 g ofN-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide.

¹H-NMR (DMSO-d₆) δ: 8.92 (s, 1H), 7.98 (s, 1H), 7.84 (d, J=2.4 Hz, 1H),7.06 (dd, J=8.5, 2.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 1.25 (s, 9H)

Reference Production Example 48

A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of3-chloroisonicotinic acid, 1.04 g of(benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 gof triethylamine and 5 ml of DMF was stirred at room temperature for twohours. Water was added to the reaction mixture, precipitated solid wascollected by filtration. The resultant solid was dissolved in ethylacetate. Then, the organic layer was washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.43 g of3-chloro-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m,1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02(m, 1H), 6.98-6.94 (m, 1H)

Reference Production Example 49

A mixture of 0.72 g of 3-trifluoromethyl isonicotinic acid and 4 ml ofthionyl chloride was heated to reflux for 1.5 hours. The reactionmixture was cooled to room temperature, and the reaction mixture wasconcentrated under reduced pressure to give 3-trifluoromethylisonicotinic acid chloride. A mixture of the resultant 3-trifluoromethylisonicotinic acid chloride and 4 ml of DMF was added dropwise to amixture of 0.66 g of 2-amino-4-trifluoromethylphenol, 0.76 g oftriethylamine, 4 ml of DMF while ice-cooling. The reaction mixture wasstirred at room temperature for one hour and stirred while heating at50° C. for 2.5 hours. The reaction mixture was cooled to roomtemperature, and then water was added to the reaction mixture, followedby extraction with ethyl acetate twice. The combined organic layers werewashed with water and a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was washed with diethyl ether to give 0.62 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.06-9.04 (m, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.28-8.25(m, 1H), 7.74 (d, J=4.9 Hz, 1H), 7.41-7.37 (m, 1H), 7.06 (d, J=8.8 Hz,1H)

Reference Production Example 50

To a mixture of 10.0 g of 3-hydroxymethylpyridine and 200 ml of THF, 3.7g of 60% sodium hydride (in oil) was added in small portions at roomtemperature and then stirred for 15 minutes. To the reaction mixture,13.0 g of methyl iodide was added dropwise, and the reaction mixture wasstirred at room temperature for three hours. To the reaction mixture, 25ml of water was added. Then, the reaction mixture was concentrated underreduced pressure. To the residue, 25 ml of water was added, followed byextraction with ethyl acetate three times. The combined organic layerswere washed with a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give8.17 g of 3-methoxymethylpyridine.

¹H-NMR (CDCl₃) δ: 8.59-8.57 (m, 1H), 8.56-8.54 (m, 1H), 7.70-7.66 (m,1H), 7.31-7.27 (m, 1H), 4.47 (s, 2H), 3.41 (s, 3H)

Reference Production Example 51

A mixture of 7.74 g of 3-methoxymethylpyridine, 60 ml of acetic acid and7.5 g of 30% hydrogen peroxide solution was stirred while heating at 80°C. for four hours. The reaction mixture was cooled to room temperature,and then sodium carbonate was added in small portions. The reactionmixture was subjected to filtration, and washed with ethyl acetate. Theresultant filtrate was washed with a saturated aqueous solution ofsodium hydrogensulfite and a saturated sodium chloride solution, anddried over anhydrous sodium carbonate. Activated carbon was added,followed by filtration through Celite™. The filtrate was concentratedunder reduced pressure to give 2.66 g of 3-methoxymethylpyridineN-oxide.

¹H-NMR (CDCl₃) δ: 8.24-8.21 (m, 1H), 8.16-8.13 (m, 1H), 7.29-7.22 (m,2H), 4.43 (s, 2H), 3.43 (s, 3H)

Reference Production Example 52

A mixture of 2.66 g of 3-methoxymethylpyridine N-oxide and 9.0 g ofiodoethane was stirred while heating at 60° C. for one hour. Thereaction mixture was cooled to room temperature, diethyl ether was addedthereto. Precipitated crystals were collected by filtration. To amixture of the resultant solid and 20 ml of water, a mixture of 1.80 gof sodium cyanide and 7 ml of water was added dropwise at 50° C., andthe reaction mixture was stirred while heating at the same temperaturefor one hour. The reaction mixture was cooled to room temperature,followed by extraction with diethyl ether three times. The combinedorganic layers were washed with a saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.89 g of 3-methoxymethyl isonicotinonitrile.

¹H-NMR (CDCl₃) δ: 8.86 (d, J=0.7 Hz, 1H), 8.73 (d, J=4.9 Hz, 1H), 7.53(dd, J=4.9, 0.7 Hz, 1H), 4.66 (s, 2H), 3.51 (s, 3H)

Reference Production Example 53

A mixture of 0.89 g of 3-methoxymethyl isonicotinonitrile, 0.72 g ofsodium hydroxide, 6 ml of ethanol and 6 ml of water was heated to refluxfor three hours. The reaction mixture was cooled to room temperature,and concentrated under reduced pressure. 3 Mhydrochloric acid was addedso that pH of the resultant residue became about 3. The reaction mixturewas concentrated under reduced pressure. To the resultant solid, 40 mlof ethanol was added. The mixture was heated to reflux for five minutes,and subjected to hot filtration. The solid collected by filtration wassubjected to the same operation twice by using 40 ml each of ethanol.Combined filtrates were concentrated to give 1.0 g of 3-methoxyisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 8.77-8.75 (m, 1H), 8.67 (d, J=5.1 Hz, 1H), 7.72-7.69(m, 1H), 4.75 (s, 2H), 3.35 (s, 3H)

Reference Production Example 54

A mixture of 0.40 g of 2-amino-4-(trifluoromethyl)phenol, 0.38 g of3-methoxymethyl isonicotinic acid, 1.30 g of BOP reagent, 0.30 g oftriethylamine, and 20 ml of DMF was stirred at room temperature for fourhours. Water was added to the reaction mixture, and the reaction mixturewas extracted with ethyl acetate twice. The combined organic layers werewashed with a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.64 g ofN-[2-hydroxy-5-(trifluoromethyl)phenyl]-3(methoxymethyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 10.89 (br s, 1H), 10.00 (br s, 1H), 8.70 (s, 1H),8.69 (d, J=4.9 Hz, 1H), 8.32-8.30 (m, 1H), 7.60 (d, J=4.9 Hz, 1H),7.42-7.38 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 4.63 (s, 2H), 3.33 (s, 3H)

Reference Production Example 55

A mixture of 3.13 g of 2-hydroxy-3-nitro-5-trifluoromethylpyridine, 40ml of methanol and 0.85 g of 5% palladium on carbon was stirred underabout one atmosphere of hydrogen at room temperature for two hours. Thereaction mixture was filtered through Celite™. The filtrate wasconcentrated under reduced pressure to give 2.66 g of3-amino-2-hydroxy-5-trifluoromethylpyridine.

¹H-NMR (DMSO-d₆) δ: 11.83 (br s, 1H), 7.11-7.08 (m, 1H), 6.49-6.48 (m,1H), 5.50 (br s, 2H)

Reference Production Example 56

A mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.69g of isonicotinic acid, 1.40 g of WSC and 7 ml of pyridine was stirredwhile heating at 80° C. for two hours. The reaction mixture was cooledto room temperature, and then water was added to the reaction mixture,followed by extraction with ethyl acetate three times. The combinedorganic layers were washed with water and a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 1.22 g ofN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 9.76 (s, 1H), 8.79 (dd, J=4.5, 1.6Hz, 2H), 8.44 (d, J=2.4 Hz, 1H), 7.85-7.81 (m, 3H)

Reference Production Example 57

A mixture of 0.88 g of 3-chloroisonicotinic acid, 5 ml of thionylchloride and 20 mg of DMF was heated to reflux for three hours. Afterthe reaction mixture was cooled to room temperature, it was concentratedunder reduced pressure to give 3-chloroisonicotinic acid chloride. Theresultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was addeddropwise to a mixture of 1.0 g of3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and8 ml of DMF while ice-cooling. The reaction mixture was stirred at roomtemperature for one hour, and then stirred while heating at 50° C. for30 minutes. The reaction mixture was cooled to room temperature, andthen water was added to the reaction mixture, followed by extractionwith ethyl acetate twice. The combined organic layers were washed withwater and a saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography to give 0.87 g of3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.

¹H-NMR (CDCl₃) δ: 12.59 (br s, 1H), 9.18 (br s, 1H), 8.85-8.83 (m, 1H),8.77 (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 7.69 (d, J=4.9 Hz, 1H), 7.55-7.53(m, 1H)

Reference Production Example 58

3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 57 using 3-fluoroisonicotinic acid instead of3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.78 (br s, 1H), 10.10 (d, J=5.6 Hz, 1H), 8.78 (d,J=2.2 Hz, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H), 7.84-7.82(m, 1H), 7.80-7.77 (m, 1H)

Reference Production Example 59

N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methylisonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 578 using methyl isonicotinic acid instead of3-chloroisonicotinic acid.

¹H-NMR (CDCl₃) δ: 12.79 (br s, 1H), 8.81-8.79 (m, 1H), 8.73-8.70 (m,1H), 8.63-8.60 (m, 2H), 7.56-7.54 (m, 1H), 7.43-7.41 (m, 1H), 2.53 (s,3H)

Reference Production Example 60

3-ethyl-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide wasobtained according to the same manner as that of Reference ProductionExample 57 using 3-ethyl isonicotinic acid instead of3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 9.87 (br s, 1H), 8.57 (s, 1H),8.52 (d, J=4.8 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.82-7.79 (m, 1H), 7.41(d, J=4.8 Hz, 1H), 2.73 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H)

Reference Production Example 61

N-(2-hydroxy-5-trifluoromethylpyridin-3-yl)-3-tri fluoromethylisonicotinami de was obtained according to the same manner as that ofReference Production Example 57 using 3-trifluoromethyl isonicotinicacid instead of 3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 10.54 (br s, 1H), 9.02 (s, 1H),8.95 (d, J=5.1 Hz, 1H), 8.48 (d, J=2.7 Hz, 1H), 7.83-7.80 (m, 1H), 7.69(d, J=5.1 Hz, 1H)

Reference Production Example 62

A mixture of 1.73 g of 3-methoxyisonicotinonitrile, 1.03 g of sodiumhydroxide and 20 ml of ethanol was heated to reflux for 20 hours. Themixture was cooled to room temperature, and then concentrated underreduced pressure. 3 M hydrochloric acid was added so that pH of theresultant residue became about 3, and the residue was concentrated underreduced pressure again. To the resultant solid, 40 ml of ethanol wasadded. The reaction mixture was heated to reflux for five minutes, andsubjected to hot filtration. The solid collected by filtration wassubjected to the same operation twice by using 40 ml each of ethanol.The combined filtrates were concentrated to give 1.97 g of 3-methoxyisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 8.55 (s, 1H), 8.30 (d, J=4.9 Hz, 1H), 7.53 (d, J=4.7Hz, 1H), 3.94 (s, 3H)

Reference Production Example 63

N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methoxyisonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 57 using 3-methoxy isonicotinic acid instead of3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.74 (br s, 1H), 10.83 (br s, 1H), 8.73 (s, 1H),8.57-8.55 (m, 1H), 8.44 (d, J=4.9 Hz, 1H), 7.89 (d, J=4.9 Hz, 1H),7.81-7.77 (m, 1H), 4.18 (s, 3H)

Reference Production Example 64

To a mixture of 2.0 g of 3-chloroisonicotinonitrile and 8 ml of DMF,1.02 g of sodium thiomethoxide was added while ice-cooling. The reactionmixture was stirred at 0° C. for one hour. The reaction mixture wasconcentrated under reduced pressure, to which ethyl acetate was addedfor filtering out insoluble matters. Filtrates were concentrated underreduced pressure, and the resultant residue was subjected to silica gelcolumn chromatography to give 2.11 g of 3-methylthioisonicotinonitrile.

¹H-NMR (CDCl₃) δ: 8.65 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 7.46-7.44 (m,1H), 2.66 (s, 3H)

Reference Production Example 65

3-methylthioisonicotinic acid was obtained according to the same manneras that of Reference Production Example 62 using3-methylthioisonicotinonitrile instead of 3-methoxyisonicotinonitrile.

¹H-NMR (DMSO-d₆) δ: 13.73 (br s, 1H), 8.62 (s, 1H), 8.46 (d, J=5.1 Hz,1H), 7.70 (d, J=5.0 Hz, 1H), 2.54 (s, 3H)

Reference Production Example 66

N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-methylthioisonicotinamide was obtained according to the same manner as that ofReference Production Example 57 using 3-methylthioisonicotinic acidinstead of 3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.68 (br s, 1H), 10.00 (br s, 1H), 8.65 (s, 1H),8.49 (d, J=4.9 Hz, 1H), 8.47-8.45 (m, 1H), 7.82-7.78 (m, 1H), 7.50-7.48(m, 1H), 2.55 (s, 3H)

Reference Production Example 67

3-ethylthioisonicotinonitrile was obtained according to the same manneras that of Reference Production Example 64 using sodium thioethoxideinstead of sodium thiomethoxide.

¹H-NMR (CDCl₃) δ: 8.73 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 7.47 (d, J=4.8Hz, 1H), 3.13 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H)

Reference Production Example 68

3-ethylthio isonicotinic acid was obtained according to the same manneras that of Reference Production Example 62 using3-ethylthioisonicotinonitrile instead of 3-methoxyisonicotinonitrile.

¹H-NMR (DMSO-d₆) δ: 13.72 (br s, 1H), 8.65 (s, 1H), 8.45 (d, J=5.1 Hz,1H), 7.67 (d, J=5.0 Hz, 1H), 3.09 (q, J=7.3 Hz, 2H), 1.27 (t, J=7.4 Hz,3H)

Reference Production Example 69

N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-ethylthioisonicotinamide was obtained according to the same manner as that ofReference Production Example 57 using 3-ethylthio isonicotinic acidinstead of 3-chloroisonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 10.11 (br s, 1H), 8.70 (s, 1H),8.52 (d, J=4.9 Hz, 1H), 8.49-8.47 (m, 1H), 7.82-7.79 (m, 1H), 7.50 (d,J=5.0 Hz, 1H), 3.04 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.3 Hz, 3H)

Reference Production Example 70

A mixture of 0.51 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.48g of 3-methoxymethyl isonicotinic acid, 1.65 g of BOP reagent, 0.38 g oftriethylamine and 6 ml of DMF was stirred at room temperature for onehour, and further stirred while heating at 50° C. for two hours. Waterwas added to the reaction mixture, followed by extraction with ethylacetate twice. The combined organic layers were washed with a saturatedsodium chloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography to give 0.58 g ofN-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-(methoxymethyl)isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 10.18 (br s, 1H), 8.71-8.67 (m,2H), 8.54-8.51 (m, 1H), 7.80 (s, 1H), 7.58 (d, J=4.8 Hz, 1H), 4.58 (s,2H), 3.33 (s, 3H)

Reference Production Example 71

To a mixture of 0.80 g of 3-amino-2-hydroxy-6-trifluoromethylpyridine,1.14 g of triethylamine and 10 ml of DMF, 0.88 g of isonicotinic acidchloride hydrochloride was added while ice-cooling. The reaction mixturewas stirred at room temperature for one hour and further stirred whileheating at 50° C. for one hour. To the reaction mixture, 0.88 g ofisonicotinic acid chloride hydrochloride and 1.1 g of triethylamine wereadded, and the reaction mixture was stirred while heating at 50° C. forfurther 1.5 hours. The reaction mixture was cooled to room temperature,and water was added to the reaction mixture. Precipitated crystals werecollected by filtration. The resultant solid was dissolved in ethylacetate, then washed with a saturated sodium chloride solution, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel column chromatographyto give 0.91 g ofN-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-isonicotinamide.

¹H-NMR (DMSO-d₆) δ: 9.98 (br s, 1H), 8.79 (dd, J=4.4, 1.5 Hz, 2H), 8.39(d, J=7.8 Hz, 1H), 7.85 (dd, J=4.5, 1.6 Hz, 2H), 7.40-7.19 (m, 1H)

Reference Production Example 72

N-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-3-chloroisonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 57 using 3-amino-2-hydroxy-6-trifluoromethylpyridineinstead of 3-amino-2-hydroxy-5-trifluoromethylpyridine.

¹H-NMR (DMSO-d₆) δ: 10.47 (br s, 1H), 8.74 (s, 1H), 8.63 (d, J=4.9 Hz,1H), 8.57 (s, 1H), 7.60 (d, J=4.8 Hz, 1H), 7.51-7.31 (m, 1H)

Reference Production Example 73

2-amino-6-methylpyridin-3-ol was obtained according to the same manneras that of Reference Production Example 1 using6-methyl-2-nitropyridin-3-ol instead of 4-propyl-2-nitrophenol.

¹H-NMR (DMSO-d₆) δ: 9.11 (br s, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.21 (d,J=7.5 Hz, 1H), 5.30 (br s, 2H), 2.14 (s, 3H)

Reference Production Example 74

A mixture of 0.59 g of 60% sodium hydride (in oil) and 5 ml of DMF wasstirred while ice-cooling. To the reaction mixture, 1.59 g of benzylalcohol was added. The reaction mixture was stirred at the sametemperature for 10 minutes. To the reaction mixture, 2.0 g of3-chloroisonicotinonitrile was added, and the reaction mixture wasstirred at the same temperature for 30 minutes and at room temperaturefor 1.5 hours. The reaction mixture was concentrated under reducedpressure, and then to ethyl acetate was added to the reaction mixture,followed by filtration of insoluble matters. The filtrate wasconcentrated under reduced pressure and the resultant residue wassubjected to silica gel column chromatography to give 2.64 g of3-benzyloxy isonicotinonitrile.

¹H-NMR (CDCl₃) δ: 8.52 (s, 1H), 8.36 (d, J=4.6 Hz, 1H), 7.48-7.33 (m,6H), 5.33 (s, 2H)

Reference Production Example 75

3-benzyloxy isonicotinic acid was obtained according to the same manneras that of Reference Production Example 62 using 3-benzyloxyisonicotinonitrile instead of 3-methoxy isonicotinonitrile.

¹H-NMR (DMSO-d₆) δ: 13.41 (br s, 1H), 8.59 (s, 1H), 8.29 (d, J=4.6 Hz,1H), 7.53 (d, J=4.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.44-7.37 (m, 2H),7.36-7.30 (m, 1H), 5.34 (s, 2H)

Reference Production Example 76

3-benzyloxy-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-isonicotinamidewas obtained according to the same manner as that of ReferenceProduction Example 70 using 3-benzyloxy isonicotinic acid instead of3-methoxymethyl isonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 12.76 (br s, 1H), 10.80 (br s, 1H), 8.76 (s, 1H),8.57-8.55 (m, 1H), 8.38 (d, J=4.9 Hz, 1H), 7.85 (d, J=4.9 Hz, 1H), 7.79(s, 1H), 7.63-7.58 (m, 2H), 7.41-7.29 (m, 3H), 5.61 (s, 2H)

Reference Production Example 77

A mixture of 10.0 g of 3-ethylpyridine, 60 ml of acetic acid and 12 mlof 30% hydrogen peroxide solution was stirred while heating at 80° C.for 2.5 hours. To the reaction mixture, 7 ml of 30% hydrogen peroxidesolution was added, and the reaction mixture was stirred while heatingat 80° C. for further seven hours. The reaction mixture was cooled toroom temperature, and sodium carbonate was added to the reaction mixturein small portions. The reaction mixture was filtered, and washed withethyl acetate. The resultant filtrate was washed with a saturatedaqueous solution of sodium hydrogensulfite and a saturated sodiumchloride solution, dried over anhydrous water sodium carbonate.Activated carbon was added, followed by filtration through Celite™. Thefiltrate was concentrated under reduced pressure to give 6.0 g of3-ethylpyridine N-oxide.

¹H-NMR (CDCl₃) δ: 8.12 (s, 1H), 8.10-8.08 (m, 1H), 7.23-7.18 (m, 1H),7.16-7.12 (m, 1H), 2.64 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.7 Hz, 3H)

Reference Production Example 78

A mixture of 6.0 g of 3-ethylpyridine N-oxide and 23 g of iodoethane wasstirred while heating at 60° C. for one hour. The reaction mixture wascooled to room temperature, and diethyl ether was added. Precipitatedcrystal was collected by filtration. To a mixture of the resultant solidand 55 ml of water, a mixture of 4.46 g of sodium cyanide and 16 ml ofwater 16 ml was added dropwise at 50° C., and stirred while heating atthe same temperature for one hour. The reaction mixture was cooled toroom temperature, followed by extraction with diethyl ether three times.The combined organic layers were washed with a saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography to give 2.7 g of 3-ethyl isonicotinonitrile.

¹H-NMR (CDCl₃) δ: 8.69 (s, 1H), 8.61 (d, J=4.9 Hz, 1H), 7.48-7.46 (m,1H), 2.90 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H)

Reference Production Example 79

A mixture of 2.7 g of 3-ethyl isonicotinonitrile, 1.63 g of sodiumhydroxide, 20 ml of ethanol and 20 ml of water was heated to reflux forfive hours. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure. 3 M hydrochloric acid was added sothat pH of the resultant residue became about 3, which was concentratedunder reduced pressure again. To the resultant solid, 50 ml of ethanolwas added and heated to reflux for five minutes, followed by hotfiltration. To the solid collected by filtration, the same operation wascarried out by using 50 ml each of ethanol. Combined filtrates wereconcentrated to give 2.49 g of 3-ethyl isonicotinic acid.

¹H-NMR (DMSO-d₆) δ: 13.58 (br s, 1H), 8.59 (s, 1H), 8.54 (d, J=5.0 Hz,1H), 7.60 (d, J=5.0 Hz, 1H), 2.89 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.4 Hz,3H)

Next, Formulation Examples of Active compounds are shown. Note here thatpart represents part by weight.

Formulation Example 1

Ten parts of any one of the above-mentioned active compounds 1 to 162are dissolved in a mixture of 35 parts of xylene and 35 parts ofN,N-dimethylformamide. To the mixture, 14 parts of polyoxyethylenestyrylphenyl ether and 6 parts of calcium dodecylbenzenesulfonate areadded. The mixture is well stirred and mixed to give 10% emulsion foreach of the active compounds.

Formulation Example 2

Twenty parts of any one of the above-mentioned active compounds 1 to 162are added to a mixture of 4 parts of sodium lauryl sulfate, 2 parts ofcalcium lignin sulfonate, 20 parts of fine powder of water-containingsynthetic silicon oxide and 54 parts of diatomite. The mixture is wellstirred and mixed to give 20% wettable powder for each of the activecompounds.

Formulation Example 3

To 2 parts of any one of the above-mentioned active compounds 1 to 162,1 part of fine powder of water-containing synthetic silicon oxide, 2parts of calcium lignin sulfonate, 30 parts of bentonite and 65 parts ofkaolin clay are added, followed by sufficient stirring and mixing. Then,a suitable amount of water is added to the mixture. The mixture isfurther stirred, granulated by a granulator, and air-dried to give 2%granules for each of the active compounds.

Formulation Example 4

One part of any one of the above-mentioned active compounds 1 to 162 isdissolved in a suitable amount of acetone. To the solution, 5 parts offine powder of synthesized hydrated silicon oxide, 0.3 parts of PAP(isopropyl phosphate) and 93.7 parts of Fubasami clay are added. Themixture solution is sufficiently stirred and mixed, and acetone isremoved by evaporation to give 1% dusting powder formulation for each ofthe active compounds.

Formulation Example 5

Thirty-five parts of mixture of polyoxyethylene alkyl ether sulfateammonium salt and white carbon (weight ratio of 1:1), 10 parts of anyone of the above-mentioned active compounds 1 to 162, and 55 parts ofwater are mixed. The mixture is pulverized by wet method to give 10%flowables for each of the active compounds.

Formulation Example 6

0.1 parts of any one of the above-mentioned active compounds 1 to 162 isdissolved in 5 parts of xylene and 5 parts of trichloroethane, which ismixed with 89.9 parts of deodorized kerosene to give 0.1% oil solutionfor each of the active compounds.

Formulation Example 7

10 mg of any one of the above-mentioned active compounds 1 to 162 isdissolved in 0.5 ml of acetone. The solution is treated into 5 g ofsolid feed powder for animals (Breeding Solid Feed Powder CE-2,available from Japan Clea Co., Ltd.) and mixed homogeneously. Then,acetone is removed by evaporation to give a poisonous bait for each ofthe active compounds.

Formulation Example 8

0.1 parts of any one of the above-mentioned active compounds 1 to 162and 49.9 parts of Neo-chiozol (Chuo Kasei Co., Ltd.) are put into anaerosol can, to which an aerosol valve is attached. Then, 25 parts ofdimethyl ether and 25 parts of LPG are filled in the aerosol can,followed by shaking and attachment of an actuator. Thus, an oil-basedaerosol is obtained.

Formulation Example 9

0.6 parts of any one of the above-mentioned active compounds 1 to 162,0.01 parts of BHT (2,6-di-tert-butyl-4-methylphenol), 5 parts of xylene,3.39 parts of deodorized kerosene and 1 part of emulsifier {Atmos 300(registered trade name for ATMOS CHEMICAL LTD)} are mixed and dissolved.The mixture solution and 50 parts of distilled water are filled in anaerosol container, and a valve is fixed to the container. 40 parts ofpropellant (LPG) are charged under pressure through the valve to give anaqueous aerosol.

Formulation Example 10

Ten parts of any one of the above-mentioned active compounds 1 to 162,and 10 parts of substances that can be mixed and formulated with theactive compound, for example, insecticide, acaricide, nematicide orantimicrobial agent, plant hormone, plant growth substance, herbicide,and the like, harmful organism controlling agent (containing isomers andsalt thereof) such as herbicide, synergist, or agents for reducingdrug-induced sufferings are added to a mixture of 4 parts of sodiumlauryl sulfate, 2 parts of calcium lignin sulfonate, 20 parts of finepowder of synthesized hydrated silicon oxide and 54 parts of diatomite.The mixture is well stirred and mixed to give mixed wettable powder.

Next, arthropod pest control effects of active compounds are shown byTest Examples.

Test Example 1

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compounds 1 to 3, theactive compound 5, the active compound 6, the active compounds 8 to 16,the active compounds 18 to 20, the active compounds 23 to 25, the activecompounds 27 to 32, the active compound 34, the active compound 35, theactive compound 37, the active compounds 39 to 44, the active compound46, the active compounds 52 to 58, the active compound 61, the activecompounds 63 to 74, the active compounds 76 to 79, the active compounds81 to 86, the active compound 88, the active compound 89, the activecompounds 91 to 94, the active compound 97, the active compound 98, theactive compound 100, the active compound 101, the active compound 104,the active compound 105, the active compound 110, the active compound111, the active compound 115, the active compound 116, the activecompounds 118 to 120, the active compound 122, the active compound 125,the active compound 126, the active compounds 128 to 136 and the activecompounds 138 to 145. The formulations were diluted with water so thatthe concentration of the active ingredient became 500 ppm and thus testdiluents were prepared.

On the other hand, a cucumber seedling (second true leaf developmentstage) planted in a plastic cup was inoculated with about 30 cottonaphids (Aphis gossypii Glover) and allowed to stand for one day. To theseedling, any one of the diluents (10 ml) was scattered.

Five days after the scattering, the number of survived cotton aphidsparasitic on the cucumber leaves was counted, and the control value wascalculated by the following equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: the number of insects in non-treated section before treatment

Cai: the number of insects in non-treated section during observation

Tb: the number of insects in treated section before treatment

Tai: the number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compounds 1 to 3, the active compound 5, theactive compound 6, the active compounds 8 to 16, the active compounds 18to 20, the active compounds 23 to 25, the active compounds 27 to 32, theactive compound 34, the active compound 35, the active compound 37, theactive compounds 39 to 44, the active compound 46, the active compounds52 to 58, the active compound 61, the active compounds 63 to 74, theactive compounds 76 to 79, the active compounds 81 to 86, the activecompound 88, the active compound 89, the active compounds 91 to 94, theactive compound 97, the active compound 98, the active compound 100, theactive compound 101, the active compound 104, the active compound 105,the active compound 110, the active compound 111, the active compound115, the active compound 116, the active compounds 118 to 120, theactive compound 122, the active compound 125, the active compound 126,the active compounds 128 to 136 and the active compounds 138 to 145showed not less than 90% of control value.

Test Example 2

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 14, the activecompound 18, the active compound 19, the active compounds 23 to 27, theactive compound 29, the active compound 30, the active compound 35, theactive compound 37, the active compound 55, the active compound 56, theactive compound 58, the active compound 63, the active compounds 69 to71, the active compound 76, the active compound 88, the active compound93, the active compound 94, the active compound 107, the active compound110, the active compound 119, the active compound 120, the activecompound 125, the active compound 126, the active compound 128, theactive compound 131, the active compounds 133 to 136, the activecompounds 138 to 150 and the active compounds 153 to 155. Theformulations were diluted with water so that the concentration of theactive ingredient became 500 ppm and thus test diluents were prepared.

On the other hand, a plant foot of cucumber seedling (second true leafdevelopment stage) planted in a urethane mat was irrigated with any oneof diluents (5 ml). One day after the treatment, the cucumber leaveswere inoculated with 30 cotton aphids (all stages). Further seven daysafter, the number of survived cotton aphids parasitic on the cucumberleaves was counted, and the control value was calculated by thefollowing equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 14, the active compound 18, the activecompound 19, the active compounds 23 to 27, the active compound 29, theactive compound 30, the active compound 35, the active compound 37, theactive compound 55, the active compound 56, the active compound 58, theactive compound 63, the active compounds 69 to 71, the active compound76, the active compound 88, the active compound 93, the active compound94, the active compound 107, the active compound 110, the activecompound 119, the active compound 120, the active compound 125, theactive compound 126, the active compound 128, the active compound 131,the active compounds 133 to 136, the active compounds 138 to 150 and theactive compounds 153 to 155 showed not less than 90% of control value.

Test Example 3

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 13, the activecompound 14, the active compound 19, the active compound 24, the activecompound 25, the active compound 30, the active compound 37, the activecompound 58, the active compound 63, the active compound 125, the activecompound 135, the active compounds 139 to 142, the active compound 144and the active compound 145. The formulations were diluted with water sothat the concentration of the active ingredient became 500 ppm and thustest diluents were prepared.

On the other hand, a plant foot of cucumber seedling (second true leafdevelopment stage) planted in a plastic cup was irrigated with any oneof diluents (5 ml). The seedling was kept in a green house of 25° C. forseven days. The cucumber leaves were inoculated with 30 cotton aphids(all stages) and kept in the green house for further six days.Thereafter, the number of survived cotton aphids parasitic on thecucumber leaves was counted, and the control value was calculated by thefollowing equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 13, the active compound 14, the activecompound 19, the active compound 24, the active compound 25, the activecompound 30, the active compound 37, the active compound 58, the activecompound 63, the active compound 125, the active compound 135, theactive compounds 139 to 142, and the active compound 144 and 145 showednot less than 90% of control value.

Test Example 4

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 1, the activecompound 3, the active compound 5, the active compound 6, the activecompound 8, the active compounds 11 to 20, the active compounds 23 to32, the active compound 34, the active compound 35, the active compound37, the active compounds 39 to 44, the active compound 46, the activecompound 52, the active compound 53, the active compounds 55 to 58, theactive compound 63, the active compounds 65 to 70, the active compounds72 to 74, the active compounds 77 to 81, the active compounds 83 to 86,the active compound 88, the active compound 89, the active compounds 91to 94, the active compound 97, the active compound 98, the activecompound 100, the active compound 101, the active compound 104, theactive compound 105, the active compound 107, the active compound 110,the active compound 111, the active compounds 115 to 120, the activecompound 122, the active compound 123, the active compound 125, theactive compound 126, the active compounds 128 to 136, the activecompounds 138 to 145, the active compounds 153 and the active compound154. The formulations were diluted with water so that the concentrationof the active ingredient became 500 ppm and thus test diluents wereprepared.

On the other hand, by releasing tobacco whitefly imagos to a tomatoseedling planted in a plastic cup to allow them to lay eggs for about 24hours. The tomato seedling was kept in a green house for eight days. Atthe stage in which larvae hatched from the laid eggs, any of the testdiluents was scattered at the rate of 10 ml/cup. The tomato seedling waskept in the greenhouse at 25° C. for seven days. The number of survivedlarvae on tomato leaves was counted, and the control value wascalculated by the following equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 1, the active compound 3, the activecompound 5, the active compound 6, the active compound 8, the activecompounds 11 to 20, the active compounds 23 to 32, the active compound34, the active compound 35, the active compound 37, the active compounds39 to 44, the active compound 46, the active compound 52, the activecompound 53, the active compounds 55 to 58, the active compound 63, theactive compounds 65 to 70, the active compounds 72 to 74, the activecompounds 77 to 81, the active compounds 83 to 86, the active compound88, the active compound 89, the active compounds 91 to 94, the activecompound 97, the active compound 98, the active compound 100, the activecompound 101, the active compound 104, the active compound 105, theactive compound 107, the active compound 110, the active compound III,the active compounds 115 to 120, the active compound 122, the activecompound 123, the active compound 125, the active compound 126, theactive compounds 128 to 136, the active compounds 138 to 145, the activecompound 153 and the active compound 154 showed not less than 90% ofcontrol value.

Test Example 5

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 1, the activecompounds 4 to 6, the active compound 8, the active compounds 12 to 15,the active compounds 18 to 20, the active compounds 24 to 30, the activecompound 32, the active compound 34, the active compound 35, the activecompounds 37 to 44, the active compound 46, the active compounds 52 to54, the active compound 58, the active compound 59, the active compound61, the active compound 67, the active compound 68, the active compounds71 to 86, the active compound 88, the active compound 89, the activecompounds 91 to 94, the active compound 97, the active compound 98, theactive compounds 100 to 105, the active compound 107, the activecompounds 110 to 113, the active compounds 115 to 120, the activecompound 122, the active compound 123, the active compounds 125 to 136,the active compound 138, the active compound 139 and the activecompounds 142 to 145. The formulations were diluted with water so thatthe concentration of the active ingredient became 500 ppm and thus testdiluents were prepared.

On the other hand, to a rice plant seedling (two weeks after seeding,second leaf development stage) planted in a plastic cup, any one of thediluents (10 ml) was scattered. After the drug solution scattered on therice plant was dried, 30 first-instars of rice brown planthopper werereleased on the rice plant, which was kept in the green house at 25° C.for six days. Thereafter, the number of rice brown planthopper parasiticon rice plant was counted and the control value was calculated by thefollowing equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 1, the active compounds 4 to 6, theactive compound 8, the active compounds 12 to 15, the active compounds18 to 20, the active compounds 24 to 30, the active compound 32, theactive compound 34, the active compound 35, the active compounds 37 to44, the active compound 46, the active compounds 52 to 54, the activecompound 58, the active compound 59, the active compound 61, the activecompound 67, the active compound 68, the active compounds 71 to 86, theactive compound 88, the active compound 89, the active compounds 91 to94, the active compound 97, the active compound 98, the active compounds100 to 105, the active compound 107, the active compounds 110 to 113,the active compounds 115 to 120, the active compound 122, the activecompound 123, the active compounds 125 to 136, the active compound 138,the active compound 139 and the active compounds 142 to 145 showed notless than 90% of control value.

Test Example 6

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 14, the activecompound 18, the active compound 24, the active compound 25, the activecompound 30, the active compound 35, the active compound 37, the activecompound 39, the active compound 41, the active compound 44, the activecompound 46, the active compound 58, the active compounds 69 to 72, theactive compound 75, the active compound 92, the active compound 93, theactive compound 97, the active compound 98, the active compound 100, theactive compound 101, the active compound 107, the active compound 110,the active compound 111, the active compounds 116 to 120, the activecompound 125, the active compound 126, the active compound 139 and theactive compounds 142 to 144. The formulations were diluted with water sothat the concentration of the active ingredient became 500 ppm and thustest diluents were prepared.

On the other hand, a plant foot of rice plant seedling (two weeks afterseeding, second leaf development stage) planted in a plastic cup wasirrigated with any one of diluents (5 ml). The seedling was kept in agreen house of 25° C. for seven days. Thirty first-instars of rice brownplanthopper were released to the seedling, which was kept in the greenhouse at 25° C. for six days. Thereafter, the number of survived ricebrown planthopper parasitic on rice plant leaves was counted, and thecontrol value was calculated by the following equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 14, the active compound 18, the activecompound 24, the active compound 25, the active compound 30, the activecompound 35, the active compound 37, the active compound 39, the activecompound 41, the active compound 44, the active compound 46, the activecompound 58, the active compounds 69 to 72, the active compound 75, theactive compound 92, the active compound 93, the active compound 97, theactive compound 98, the active compound 100, the active compound 101,the active compound 107, the active compound 110, the active compound111, the active compounds 116 to 120, the active compound 125, theactive compound 126, the active compound 139 and the active compounds142 to 144 showed not less than 90% of control value.

Test Example 7

Formulations were prepared by the method described in FormulationExample 1 with respect to each of the active compound 13, the activecompound 15, the active compound 18, the active compound 35, the activecompound 37, the active compound 44, the active compound 65, the activecompound 68 and the active compound 82. The formulations were dilutedwith water so that the concentration of the active ingredient became 100ppm and thus test diluents were prepared.

On the other hand, a tissue paper placed in an aluminum cup wasirrigated with any one of the above-mentioned diluents (5 ml). Thetissue paper was placed in a polyethylene cup together with threebudding soybeans. In the polyethylene cup, ten halymorpha halys werereleased, and the polyethylene cup was lidded by a polyethylene lid.Seven days after the releasing of the insects, the number of survivedinsects was counted, and the mortality was calculated by the followingequation.

Mortality (%)=(number of dead insects/number of insects to betested)×100

As a result, the treated sections treated with any one of the testdiluents of the active compound 13, the active compound 15, the activecompound 18, the active compound 35, the active compound 37, the activecompound 44, the active compound 65, the active compound 68 and theactive compound 82 showed not less than 80% of mortality.

Test Example 8

Formulations were prepared by the method described in FormulationExample 5 with respect to each of the active compound 2 and the activecompound 13. The formulations were diluted with water so that theconcentration of the active ingredient became 200 ppm and thus testdiluents were prepared.

On the other hand, a cucumber seedling (second true leaf developmentstage) planted in a plastic cup was inoculated with about 30 cottonaphids and allowed to stand for one day. To the seedling, any one of thediluents (10 ml) was scattered.

Five days after scattering, the number of survived cotton aphidsparasitic on the cucumber leaves was counted, and the control value wascalculated by the following equation.

Control value (%)={1−(Cb×Tai)/(Cai×Tb)}×100

wherein each character represents the following meaning:

Cb: number of insects in non-treated section before treatment

Cai: number of insects in non-treated section during observation

Tb: number of insects in treated section before treatment

Tai: number of insects in treated section during observation

As a result, the treated sections treated with any one of the testdiluents of the active compound 2 and the active compound 13 showed notless than 90% of control value.

Comparative Test Example

A compound shown in the following formula (B) disclosed in Chem. Pharm.Bull., 30(8), 2996 (1982) (hereinafter, referred to as comparativecompound (B)) was subjected to the same test as in Test Example 8. Thetreated section treated with the test scattering solution of comparativecompound (B) showed control value of less than 30%.

INDUSTRIAL APPLICABILITY

A composition of the present invention has an excellent control effecton arthropod pests and is useful.

1. An arthropod pest control composition comprising a carrier and, as anactive ingredient, a compound represented by formula (1):

wherein each of A¹ and A² independently represents a nitrogen atom or═C(R⁷)—; each of R¹ and R⁴ independently represents a halogen atom or ahydrogen atom; each of R² and R³ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;—OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸;—CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group;a nitro group; a halogen atom; or a hydrogen atom; R⁵ and R⁶, togetherwith 6-membered ring constituent atoms to which they bind, form a 5- or6-membered ring optionally substituted with one or more members selectedfrom Group Z; R⁷ represents a C1-C3 alkyl group optionally substitutedwith one or more halogen atoms; a C1-C3 alkoxy group optionallysubstituted with one or more halogen atoms; a cyano group; a halogenatom; or a hydrogen atom; each of R⁸ and R⁹ independently represents aC1-C6 acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C4-C7 cycloalkylmethyl group optionallysubstituted with one or more members selected from Group X; a C3-C6alicyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a phenyl group optionally substitutedwith one or more members selected from Group Y; a benzyl groupoptionally substituted with one or more members selected from Group Y; a5- or 6-membered heterocyclic group optionally substituted with one ormore members selected from Group Y; or a hydrogen atom; provided that R⁸does not represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2; eachof R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; or a hydrogen atom; each ofR¹¹ and R¹² independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C2-C4 alkoxycarbonylgroup; or a hydrogen atom; R¹⁵ represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; m represents 0, 1, or 2; nrepresents 0 or 1; Group X represents one selected from the groupconsisting of a C1-C4 alkoxy group optionally substituted with one ormore halogen atoms; a cyano group; and a halogen atom; Group Yrepresents one selected from the group consisting of a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C1-C4 alkoxygroup optionally substituted with one or more halogen atoms; a cyanogroup; a nitro group; and a halogen atom; and Group Z represents oneselected from the group consisting of a C1-C3 alkyl group optionallysubstituted with one or more halogen atoms; and a halogen atom.
 2. Thearthropod pest control composition according to claim 1, wherein in thecompound each of R² and R³ independently represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; a C3-C6 alicyclic hydrocarbon group optionallysubstituted with one or more members selected from Group X; a phenylgroup optionally substituted with one or more members selected fromGroup Y; a benzyl group optionally substituted with one or more membersselected from Group Y; a 5- or 6-membered heterocyclic group optionallysubstituted with one or more members selected from Group Y; —OR⁸;—NR⁸R⁹; —NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —CONR¹⁰NR¹¹R¹²; acyano group; a nitro group; a halogen atom; or a hydrogen atom; and eachof R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aC3-C6 alicyclic hydrocarbon group optionally substituted with one ormore members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a 5- or6-membered heterocyclic group optionally substituted with one or moremembers selected from Group Y; or a hydrogen atom.
 3. The arthropod pestcontrol composition according to claim 1, wherein in the compound eachof R¹ and R⁴ represents a hydrogen atom.
 4. The arthropod pest controlcomposition according to claim 1, wherein in the compound R² representsa hydrogen atom or a halogen atom.
 5. The arthropod pest controlcomposition according to claim 1, wherein in the compound R³ representsa C3-C6 alicyclic hydrocarbon group optionally substituted with one ormore members selected from Group X; a phenyl group optionallysubstituted with one or more members selected from Group Y; a benzylgroup optionally substituted with one or more members selected fromGroup Y; or a 5- or 6-membered heterocyclic group optionally substitutedwith one or more members selected from Group Y.
 6. The arthropod pestcontrol composition according to claim 1, wherein in the compound R³represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X; —OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹;—NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰;—C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogenatom; or a hydrogen atom; and each of R⁸ and R⁹ independently representsa C1-C6 acyclic hydrocarbon group optionally substituted with one ormore members selected from Group X; or a hydrogen atom; provided that R⁸represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X when m in —S(O)_(m)R⁸ is 1 or2.
 7. The arthropod pest control composition according to claim 1,wherein in the compound R³ represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X;—OR⁸; —NR⁸R⁹; —S(O)_(m)R⁸; a halogen atom; or a hydrogen atom; and eachof R⁸ and R⁹ independently represents a C1-C6 acyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X;or a hydrogen atom; provided that R⁸ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X when m in —S(O)_(m)R⁸ is 1 or
 2. 8. (canceled) 9.An arthropod pest control method, which comprises applying, to arthropodpests or areas where arthropod pests live, an arthropod pest controlcomposition comprising a carrier and, as an active ingredient, aneffective amount of a compound represented by formula (1):

wherein each of A¹ and A² independently represents a nitrogen atom or═C(R⁷)—; each of R¹ and R⁴ independently represents a halogen atom or ahydrogen atom; each of R² and R³ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;—OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸;—CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group;a nitro group; a halogen atom; or a hydrogen atom; R⁵ and R⁶, togetherwith 6-membered ring constituent atoms to which they bind, form a 5- or6-membered ring optionally substituted with one or more members selectedfrom Group Z; R⁷ represents a C1-C3 alkyl group optionally substitutedwith one or more halogen atoms; a C1-C3 alkoxy group optionallysubstituted with one or more halogen atoms; a cyano group; a halogenatom; or a hydrogen atom; each of R⁸ and R⁹ independently represents aC1-C6 acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C4-C7 cycloalkylmethyl group optionallysubstituted with one or more members selected from Group X; a C3-C6alicyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a phenyl group optionally substitutedwith one or more members selected from Group Y; a benzyl groupoptionally substituted with one or more members selected from Group Y; a5- or 6-membered heterocyclic group optionally substituted with one ormore members selected from Group Y; or a hydrogen atom; provided that R⁸does not represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2; eachof R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; or a hydrogen atom; each ofR¹¹ and R¹² independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C2-C4 alkoxycarbonylgroup; or a hydrogen atom; R¹⁵ represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; m represents 0, 1, or 2; nrepresents 0 or 1; Group X represents one selected from the groupconsisting of a C1-C4 alkoxy group optionally substituted with one ormore halogen atoms; a cyano group; and a halogen atom; Group Yrepresents one selected from the group consisting of a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C1-C4 alkoxygroup optionally substituted with one or more halogen atoms; a cyanogroup; a nitro group; and a halogen atom; and Group Z represents oneselected from the group consisting of a C1-C3 alkyl group optionallysubstituted with one or more halogen atoms; and a halogen atom.
 10. Thearthropod pest control method according to claim 9, wherein thearthropod pests are Hemiptera insect pests.
 11. A compound representedby formula (2):

wherein each of A¹ and A² independently represents a nitrogen atom or═C(R⁷)—; each of R¹ and R⁴ independently represents a halogen atom or ahydrogen atom; each of R² and R³ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;—OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴; —NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸;—CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰; —CONR¹⁰NR¹¹R¹²; a cyano group;a nitro group; a halogen atom; or a hydrogen atom; R^(5a) and R^(6a),together with 6-membered ring constituent atoms to which they bind, forma 5- or 6-membered ring which is substituted with one or more halogenatoms; R⁷ represents a C1-C3 alkyl group optionally substituted with oneor more halogen atoms; a C1-C3 alkoxy group optionally substituted withone or more halogen atoms; a cyano group; a halogen atom; or a hydrogenatom; each of R⁸ and R⁹ independently represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; a C4-C7 cycloalkylmethyl group optionallysubstituted with one or more members selected from Group X; a C3-C6alicyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a phenyl group optionally substitutedwith one or more members selected from Group Y; a benzyl groupoptionally substituted with one or more members selected from Group Y; a5- or 6-membered heterocyclic group optionally substituted with one ormore members selected from Group Y; or a hydrogen atom; provided that R⁸does not represent a hydrogen atom when m in —S(O)_(m)R⁸ is 1 or 2; eachof R¹⁰ and R¹⁴ independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; or a hydrogen atom; each ofR¹¹ and R¹² independently represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; a C2-C4 alkoxycarbonylgroup; or a hydrogen atom; R¹⁵ represents a C1-C4 alkyl group optionallysubstituted with one or more halogen atoms; m represents 0, 1, or 2; nrepresents 0 or 1; Group X represents one selected from the groupconsisting of a C1-C4 alkoxy group optionally substituted with one ormore halogen atoms; a cyano group; and a halogen atom; and Group Yrepresents one selected from the group consisting of a C1-C4 alkyl groupoptionally substituted with one or more halogen atoms; a C1-C4 alkoxygroup optionally substituted with one or more halogen atoms; a cyanogroup; a nitro group; and a halogen atom.
 12. The compound according toclaim 11, wherein each of R² and R³ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a benzyl group optionally substituted with one or moremembers selected from Group Y; a 5- or 6-membered heterocyclic groupoptionally substituted with one or more members selected from Group Y;—OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹;—CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogen atom; or ahydrogen atom; and each of R⁸ and R⁹ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; a C3-C6 alicyclic hydrocarbon groupoptionally substituted with one or more members selected from Group X; aphenyl group optionally substituted with one or more members selectedfrom Group Y; a 5- or 6-membered heterocyclic group optionallysubstituted with one or more members selected from Group Y; or ahydrogen atom; provided that R⁸ does not represent a hydrogen atom whenm in —S(O)_(m)R⁸ is 1 or
 2. 13. The compound according to claim 11,wherein each of R¹ and R⁴ represents a hydrogen atom.
 14. The compoundaccording to claim 11, wherein R² represents a hydrogen atom or ahalogen atom.
 15. The compound according to claim 11, wherein R³represents a C3-C6 alicyclic hydrocarbon group optionally substitutedwith one or more members selected from Group X; a phenyl groupoptionally substituted with one or more members selected from Group Y; abenzyl group optionally substituted with one or more members selectedfrom Group Y; or a 5- or 6-membered heterocyclic group optionallysubstituted with one or more members selected from Group Y.
 16. Thecompound according to claim 11, wherein R³ represents a C1-C6 acyclichydrocarbon group optionally substituted with one or more membersselected from Group X; —OR⁸; —NR⁸R⁹; —NR⁸C(O)R⁹; —NR¹⁰C(O)NR⁹R¹⁴;—NR¹⁰CO₂R¹⁵; —S(O)_(m)R⁸; —CO₂R¹⁰; —CONR⁸R⁹; —C(O)R¹⁰; —C(NOR⁸)R¹⁰;—CONR¹⁰NR¹¹R¹²; a cyano group; a nitro group; a halogen atom; or ahydrogen atom; and each of R⁸ and R⁹ independently represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; or a hydrogen atom; provided that R⁸represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X when m in —S(O)_(m)R⁸ is 1 or2.
 17. The compound according to claim 11, wherein R³ represents a C1-C6acyclic hydrocarbon group optionally substituted with one or moremembers selected from Group X; —OR⁸; —NR⁸R⁹; —S(O)_(m)R⁸; a halogenatom; or a hydrogen atom; and each of R⁸ and R⁹ independently representsa C1-C6 acyclic hydrocarbon group optionally substituted with one ormore members selected from Group X; or a hydrogen atom; provided that R⁸represents a C1-C6 acyclic hydrocarbon group optionally substituted withone or more members selected from Group X when m in —S(O)_(m)R⁸ is 1 or2.
 18. (canceled)